Low level light therapy for enhancement of neurologic function of a patient affected by parkinson&#39;s disease

ABSTRACT

A method of treating a patient having neurologic function affected by Parkinson&#39;s disease is provided. The method includes providing a patient having neurologic function affected by Parkinson&#39;s disease. The method further includes delivering electromagnetic radiation noninvasively through the scalp and the skull of the patient to at least one portion of the brain of the patient. The light energy has a wavelength in the visible to near-infrared wavelength range, and the wavelength, power density, and amount of the light energy delivered to the at least one portion of the brain are sufficient to reduce the severity of symptoms of Parkinson&#39;s disease in the patient.

CLAIM OF PRIORITY

This application also claims the benefit of U.S. Provisional ApplicationNo. 60/840,370, filed Aug. 24, 2006, which is incorporated in itsentirety by reference herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present application relates to systems and methods for enhancingneurologic function such as may be desired in individuals having a lossof such function, including motor function and cognitive function,including that resulting from Parkinson's disease.

2. Description of the Related Art

Parkinson's disease is a chronic, progressive neurodegenerative diseaseor movement disorder that affects up to one million people in the UnitedStates. Parkinson's disease affects neurologic function by degradingmotor skills of the subject and by causing dementia. The pathology ofParkinson's disease includes reduced formation and action of dopamine,which is produced in the dopaminergic neurons of the brain. Previousresearch of the causes and possible treatments of Parkinson's diseasehave been directed towards efforts to compensate for the reducedformation and action of dopamine caused by the disease.

Dementia (e.g., as resulting from Parkinson's disease) is a collectionof symptoms but it is not itself a disease. It is characterized as theloss of cognitive function having a severity so as to interfere with aperson's daily activities. Cognitive function includes activities suchas knowing, thinking, learning, memory, perception, and judging.Symptoms of dementia can also include changes in personality, mood, andbehavior of the subject. Although, in some cases, dementia can be curedby curing the underlying disease (e.g. infection, nutritionaldeficiency, tumor), in most cases dementia is considered incurable.

High energy laser radiation is now well accepted as a surgical tool forcutting, cauterizing, and ablating biological tissue. High energy lasersare now routinely used for vaporizing superficial skin lesions and, tomake deep cuts. For a laser to be suitable for use as a surgical laser,it must provide laser energy at a power sufficient to heart tissue totemperatures over 50° C. Power outputs for surgical lasers vary from 1-5W for vaporizing superficial tissue, to about 100 W for deep cutting.

In contrast, low level laser therapy involves therapeutic administrationof laser energy to a patient at vastly lower power outputs than thoseused in high energy laser applications, resulting in desirablebiostimulatory effects while leaving tissue undamaged. For example, inrat models of myocardial infarction and ischemia-reperfusion injury, lowenergy laser irradiation reduces infarct size and left ventriculardilation, and enhances angiogenesis in the myocardium. (Yaakobi et al.,J. Appl. Physiol. 90, 2411-19 (2001)). Low level laser therapy has beendescribed for treating pain, including headache and muscle pain, andinflammation.

SUMMARY OF THE INVENTION

In certain embodiments, a method of treating a patient having neurologicfunction affected by Parkinson's disease is provided. The methodcomprises providing a patient having neurologic function affected byParkinson's disease. The method further comprises deliveringelectromagnetic radiation noninvasively through the scalp and the skullof the patient to at least one portion of the brain of the patient. Thelight energy has a wavelength in the visible to near-infrared wavelengthrange, and the wavelength, power density, and amount of the light energydelivered to the at least one portion of the brain are sufficient toreduce the severity of symptoms of Parkinson's disease in the patient.

In certain embodiments, a method of treating or preventing Parkinson'sdisease is provided. The method comprises noninvasively irradiating atleast a portion of a patient's brain with electromagnetic radiationtransmitted through the scalp. The electromagnetic radiation has a powerdensity between 0.01 mW/cm² and 100 mW/cm² at a depth of approximately 2centimeters below the dura.

In certain embodiments, a method of treating a patient is provided. Themethod comprises delivering electromagnetic radiation noninvasivelythrough the scalp and the skull to at least one portion of the brain ofthe patient. The light energy has a wavelength in the visible tonear-infrared wavelength range, and the wavelength, power density, andamount of the light energy delivered to the at least one portion of thebrain are sufficient to prevent, reduce the severity, or reduce theincidence of Parkinson's disease in the patient.

In certain embodiments, a method of preventing Parkinson's disease in apatient is provided. The method comprises providing a patient having apredisposition towards contracting Parkinson's disease. The methodfurther comprises delivering electromagnetic radiation noninvasivelythrough the scalp and the skull of the patient to at least one portionof the brain of the patient. The light energy has a wavelength in thevisible to near-infrared wavelength range, and the wavelength, powerdensity, and amount of the light energy delivered to the at least oneportion of the brain are sufficient to reduce a probability of thepatient contracting Parkinson's disease.

In certain embodiments, a method of treating the central nervous systemof a patient is provided. The method comprises identifying a patientexhibiting symptoms of damage to the central nervous system due toParkinson's disease. The method further comprises irradiating an invitro culture comprising progenitor cells with electromagnetic radiationhaving a wavelength in the visible to near-infrared wavelength range anda power density of at least about 0.01 mW/cm². The method furthercomprises implanting the irradiated cells into the central nervoussystem of the patient.

For purposes of summarizing the present invention, certain aspects,advantages, and novel features of the present invention have beendescribed herein above. It is to be understood, however, that notnecessarily all such advantages may be achieved in accordance with anyparticular embodiment of the present invention. Thus, the presentinvention may be embodied or carried out in a manner that achieves oroptimizes one advantage or group of advantages as taught herein withoutnecessarily achieving other advantages as may be taught or suggestedherein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 schematically illustrates a therapy apparatus comprising a capwhich fits securely over the patient's head.

FIG. 2 schematically illustrates a fragmentary cross-sectional viewtaken along the lines 2-2 of FIG. 1, showing one embodiment of a portionof a therapy apparatus comprising an element and its relationship to thescalp and brain.

FIG. 3 schematically illustrates an embodiment with an elementcomprising a container coupled to an inlet conduit and an outlet conduitfor the transport of a flowing material through the element.

FIG. 4A schematically illustrates a fragmentary cross-sectional viewtaken along the lines 2-2 of FIG. 1, showing another embodiment of aportion of a therapy apparatus comprising an element with a portioncontacting the scalp and a portion spaced away from the scalp.

FIG. 4B schematically illustrates a fragmentary cross-sectional viewtaken along the lines 2-2 of FIG. 1, showing an embodiment of a portionof a therapy apparatus comprising a plurality of light sources and anelement with portions contacting the scalp and portions spaced away fromthe scalp.

FIGS. 5A and 5B schematically illustrate cross-sectional views of twoembodiments of the element in accordance with FIG. 4B taken along theline 4-4.

FIGS. 6A-6C schematically illustrate an embodiment in which the lightsources are spaced away from the scalp.

FIGS. 7A and 7B schematically illustrate the diffusive effect on thelight by the element.

FIGS. 8A and 8B schematically illustrate two light beams havingdifferent cross-sections impinging a patient's scalp and propagatingthrough the patient's head to irradiate a portion of the patient's braintissue.

FIG. 9A schematically illustrates a therapy apparatus comprising a capand a light source comprising a light blanket.

FIGS. 9B and 9C schematically illustrate two embodiments of the lightblanket.

FIG. 10 schematically illustrates a therapy apparatus comprising aflexible strap and a housing.

FIG. 11 schematically illustrates a therapy apparatus comprising ahandheld probe.

FIG. 12 is a block diagram of a control circuit comprising aprogrammable controller.

FIG. 13 schematically illustrates a therapy apparatus comprising a lightsource and a controller.

FIG. 14 schematically illustrates a light source comprising a laserdiode and a galvometer with a mirror and a plurality of motors.

FIGS. 15A and 15B schematically illustrate two irradiation patterns thatare spatially shifted relative to each other.

FIG. 16 schematically illustrates an example therapy apparatus inaccordance with embodiments described herein.

FIG. 17A is a graph of the effects of laser treatment of 7.5 mW/cm² fora treatment duration of 2 minutes on a population of rabbits havingsmall clot embolic stroke.

FIG. 17B is a graph of the effects of laser treatment of 25 mW/cm² for atreatment duration of 10 minutes on a population of rabbits having smallclot embolic stroke.

FIG. 18 is a graph showing the therapeutic window for laser-inducedbehavioral improvements after small-clot embolic strokes in rabbits.

FIG. 19 schematically illustrates an example apparatus which is wearableby a patient for treating the patient's brain.

FIG. 20 schematically illustrates an example apparatus having aplurality of elements in accordance with certain embodiments describedherein.

FIG. 21 schematically illustrates an example element in an explodedview.

FIG. 22A schematically illustrates an example optical component withexample dimensions in inches.

FIGS. 22B and 22C schematically illustrate other example opticalcomponents in accordance with certain embodiments described herein.

FIG. 23 schematically illustrates an example first support ring withexample dimensions in inches.

FIG. 24 schematically illustrates an example second support ring withexample dimensions in inches.

FIG. 25 schematically illustrates an example label compatible withcertain embodiments described herein.

FIGS. 26A and 26B schematically illustrate an example labelingconfiguration for the apparatus on the left-side and right-side of theapparatus.

FIG. 26C schematically illustrates the example labeling configuration ofFIGS. 26A and 26B from above a flattened view of the apparatus.

FIGS. 27A-27E schematically illustrate various stages of structuresformed during the fabrication of the apparatus of FIGS. 20-25.

FIG. 28 schematically illustrates an apparatus which emits light forirradiating a patient's skin to treat portions of a patient's bodyunderneath the patient's skin.

FIG. 29 schematically illustrates an example optical conduit opticallycoupled to an example optical device.

FIG. 30 schematically illustrates a simplified optical device compatiblewith certain embodiments described herein.

FIG. 31A illustrates two beam profile cross-sections of a light beamemitted from the optical device of FIG. 29 with the planes of the twocross-sections of FIG. 31A generally perpendicular to one another and tothe output optical element.

FIG. 31B illustrates the encircled energy of a light beam emitted fromthe optical device of FIG. 29.

FIG. 32A illustrates two beam profile cross-sections of a light beamemitted from the optical device of FIG. 30 having a smooth gold-platedconical inner surface.

FIG. 32B illustrates the encircled energy of a light beam emitted fromthe optical device of FIG. 30.

FIG. 33 illustrates two beam profile cross-sections of a light beamemitted from the optical device of FIG. 30 having a grit sandblastedconical inner surface.

FIGS. 34A and 34B illustrate the beam divergence for the optical deviceof FIG. 29 and of FIG. 30 (with a sandblasted inner surface),respectively.

FIG. 35 is a flow diagram of an example method for controllably exposingat least one predetermined area of a patient's scalp to laser light toirradiate the patient's brain.

FIG. 36 is a graph which shows mediators responsible for ischemic stroketissue damage and the time points at which they occur.

FIG. 37 is a schematic diagram of the electron transport chain inmitochondria.

FIG. 38 is a graph of cell proliferation and cytochrome oxidase activitypercentage as functions of the wavelength of light used to stimulatemammalian cells.

FIG. 39 is a graph of the transmittance of light through blood (inarbitrary units) as a function of wavelength.

FIG. 40 is a graph of the absorption of light by brain tissue.

FIG. 41 is a graph of the efficiency of energy delivery as a function ofwavelength.

FIG. 42 is a bar graph of the absorption of 808 nanometer light throughvarious rat tissues.

FIG. 43 is a graph of the power density versus the depth from the durafor an input power density of 10 mW/cm².

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Certain embodiments described herein for low level light therapy methodsfor enhancing neurologic function are based in part on the new andsurprising discovery that power density (i.e., power per unit area) ofthe light energy applied to tissue appears to be a very important factorin determining the relative efficacy of low level light therapy, andparticularly with respect to enhancing the function of neurons in bothhealthy and diseased states.

Certain embodiments described herein provide methods directed toward theenhancement of neurologic function in a subject. The methods includedelivering a neurologic enhancing effective amount of a light energyhaving a wavelength in the visible to near-infrared wavelength range toat least one area of the brain of a subject. In certain embodiments,delivering the neurologic function enhancing effective amount of lightenergy includes delivering a predetermined power density of light energythrough the skull to the target area of the brain and/or deliveringlight energy through the skull to at least one area of the brain of asubject, wherein the wavelength, power density and amount of the lightenergy delivered are sufficient to cause an enhancement of neurologicfunctioning.

Low level light therapy (“LLLT”) or phototherapy involves therapeuticadministration of light energy to a patient at lower power outputs thanthose used for cutting, cauterizing, or ablating biological tissue,resulting in desirable biostimulatory effects while leaving tissueundamaged. In non-invasive phototherapy, it is desirable to apply anefficacious amount of light energy to the internal tissue to be treatedusing light sources positioned outside the body.

Laser therapy has been shown to be effective in a variety of settings,including treating lymphoedema and muscular trauma, and carpal tunnelsyndrome. Recent studies have shown that laser-generated infraredradiation is able to penetrate various tissues, including the brain, andmodify function. In addition, laser-generated infrared radiation caninduce angiogenesis, modify growth factor (transforming growth factor-β)signaling pathways, and enhance protein synthesis.

However, absorption of the light energy by intervening tissue can limitthe amount of light energy delivered to the target tissue site, whileheating the intervening tissue. In addition, scattering of the lightenergy by intervening tissue can limit the power density or energydensity delivered to the target tissue site. Brute force attempts tocircumvent these effects by increasing the power and/or power densityapplied to the outside surface of the body can result in damage (e.g.,burning) of the intervening tissue.

Non-invasive phototherapy methods are circumscribed by setting selectedtreatment parameters within specified limits so as to preferably avoiddamaging the intervening tissue. A review of the existing scientificliterature in this field would cast doubt on whether a set ofundamaging, yet efficacious, parameters could be found. However, certainembodiments, as described herein, provide devices and methods which canachieve this goal.

Such embodiments may include selecting a wavelength of light at whichthe absorption by intervening tissue is below a damaging level. Suchembodiments may also include setting the power output of the lightsource at very low, yet efficacious, power densities (e.g., betweenapproximately 100 μW/cm² to approximately 10 W/cm²) at the target tissuesite, and time periods of application of the light energy at a fewseconds to minutes to achieve an efficacious energy density at thetarget tissue site being treated. Other parameters can also be varied inthe use of phototherapy. These other parameters contribute to the lightenergy that is actually delivered to the treated tissue and may play keyroles in the efficacy of phototherapy. In certain embodiments, theirradiated portion of the brain can comprise the entire brain.

In certain embodiments, a method treats a subject suffering fromParkinson's disease. The method includes delivering light energy havinga wavelength in the visible to near-infrared wavelength range throughthe skull to at least one target area of the brain of the subject,wherein the wavelength, power density and amount of the light energydelivered are sufficient to prevent, reduce the severity, or reduce theincidence of Parkinson's disease in the subject.

In certain embodiments, the target area of the brain may be all of thebrain or a specific area of the brain including, but not limited to, anarea associated with a particular cognitive or motor function, an areaexhibiting neurodegeneration, the cortex, and/or an area that has beenaffected by trauma. The subject may have a cognitive or motor impairmentsuch as from neurodegeneration or the subject may be normal.

In certain embodiments, the predetermined power density is a powerdensity of at least about 0.01 mW/cm². The predetermined power densityin certain embodiments is typically selected from the range of about0.01 mW/cm² to about 100 mW/cm², including from about 0.01 mW/cm² toabout 15 mW/cm² and from about 2 mW/cm² to about 50 mW/cm². In certainembodiments, power densities above or below these values may be used.

In certain embodiments, the methods encompass using light energy havinga wavelength of about 630 nanometers to about 904 nanometers, and incertain embodiments the light energy has a wavelength of about 780nanometers to about 840 nanometers. The light energy is preferably froma coherent source (i.e. a laser), but light from non-coherent sourcesmay also be used.

In certain embodiments, the methods encompass placing a light source incontact with a region of skin that is either adjacent an area of thebrain in which treatment is desired, contralateral to such area, or acombination of the foregoing, and then administering the light energy,including the neurologic function enhancing effective amount of lightenergy, as may be measured by power density, to the target area of thebrain. In delivering the light, the power density may be a predeterminedpower density. In certain embodiments, a surface power density of thelight energy sufficient for the light energy to penetrate the skull isdetermined. The determination of the required surface power density,which is relatively higher than the power density to be delivered to thebrain tissue being treated, takes into account factors that attenuatepower density as it travels through tissue, including skin pigmentation,and location of the brain area being treated, particularly the distanceof the brain area from the skin surface where the light energy isapplied.

In certain embodiments, a method increases the production of adenosinetriphosphate (ATP) by neurons to increase neurologic function. Themethod comprises irradiating neurons with light energy having awavelength in the near infrared to visible portion of theelectromagnetic spectrum for at least about 1 second, where the powerdensity of said light energy at the neurons is at least about 0.01mW/cm².

While certain embodiments of phototherapy are described herein inconjunction with various theories and potential action mechanisms, asthey presently appear to the inventors, the scope of the claims of thepresent application is not to be construed to depend on the accuracy,relevance, or specifics of any of these theories or potential actionmechanisms. Thus the claims of the present application are to beconstrued without being bound by theory or by a specific mechanism.

Element to Inhibit Temperature Increases at the Scalp

FIGS. 1 and 2 schematically illustrate an embodiment of a therapyapparatus 10 for treating a patient's brain 20. The therapy apparatus 10comprises a light source 40 having an output emission area 41 positionedto irradiate a portion of the brain 20 with an efficacious power densityand wavelength of light. The therapy apparatus 10 further comprises anelement 50 interposed between the light source 40 and the patient'sscalp 30. The element 50 is adapted to inhibit temperature increases atthe scalp 30 caused by the light.

As used herein, the term “element” is used in its broadest sense,including, but not limited to, as a reference to a constituent ordistinct part of a composite device. In certain embodiments, the element50 is adapted to contact at least a portion of the patient's scalp 30,as schematically illustrated in FIGS. 1-4. In certain such embodiments,the element 50 is in thermal communication with and covers at least aportion of the scalp 30. In other embodiments, the element 50 is spacedaway from the scalp 30 and does not contact the scalp 30.

In certain embodiments, the light passes through the element 50 prior toreaching the scalp 30 such that the element 50 is in the optical path oflight propagating from the light source 40, through the scalp 30,through the bones, tissues, and fluids of the head (schematicallyillustrated in FIG. 1 by the region 22), to the brain 20. In certainembodiments, the light passes through a transmissive medium of theelement 50, while in other embodiments, the light passes through anaperture of the element 50. As described more fully below, the element50 may be utilized with various embodiments of the therapy apparatus 10.

In certain embodiments, the light source 40 is disposed on the interiorsurface of a cap 60 which fits securely over the patient's head. The cap60 provides structural integrity for the therapy apparatus 10 and holdsthe light source 40 and element 50 in place. Example materials for thecap 60 include, but are not limited to, metal, plastic, or othermaterials with appropriate structural integrity. The cap 60 may includean inner lining 62 comprising a stretchable fabric or mesh material,such as Lycra or nylon. In certain embodiments, the light source 40 isadapted to be removably attached to the cap 60 in a plurality ofpositions so that the output emission area 41 of the light source 40 canbe advantageously placed in a selected position for treatment ofParkinson's disease in any portion of the brain 20. In otherembodiments, the light source 40 can be an integral portion of the cap60.

The light source 40 illustrated by FIGS. 1 and 2 comprises at least onepower conduit 64 coupled to a power source (not shown). In someembodiments, the power conduit 64 comprises an electrical conduit whichis adapted to transmit electrical signals and power to an emitter (e.g.,laser diode or light-emitting diode). In certain embodiments, the powerconduit 64 comprises an optical conduit (e.g., optical waveguide) whichtransmits optical signals and power to the output emission area 41 ofthe light source 40. In certain such embodiments, the light source 40comprises optical elements (e.g., lenses, diffusers, and/or waveguides)which transmit at least a portion of the optical power received via theoptical conduit 64. In still other embodiments, the therapy apparatus 10contains a power source (e.g., a battery) and the power conduit 64 issubstantially internal to the therapy apparatus 10.

In certain embodiments, the patient's scalp 30 comprises hair and skinwhich cover the patient's skull. In other embodiments, at least aportion of the hair is removed prior to the phototherapy treatment, sothat the therapy apparatus 10 substantially contacts the skin of thescalp 30.

In certain embodiments, the element 50 is adapted to contact thepatient's scalp 30, thereby providing an interface between the therapyapparatus 10 and the patient's scalp 30. In certain such embodiments,the element 50 is coupled to the light source 40 and in other suchembodiments, the element is also adapted to conform to the scalp 30, asschematically illustrated in FIG. 1. In this way, the element 50positions the output emission area 41 of the light source 40 relative tothe scalp 30. In certain such embodiments, the element 50 ismechanically adjustable so as to adjust the position of the light source40 relative to the scalp 30. By fitting to the scalp 30 and holding thelight source 40 in place, the element 50 inhibits temperature increasesat the scalp 30 that would otherwise result from misplacement of thelight source 40 relative to the scalp 30. In addition, in certainembodiments, the element 50 is mechanically adjustable so as to fit thetherapy apparatus 10 to the patient's scalp 30.

In certain embodiments, the element 50 provides a reusable interfacebetween the therapy apparatus 10 and the patient's scalp 30. In suchembodiments, the element 50 can be cleaned or sterilized between uses ofthe therapy apparatus, particularly between uses by different patients.In other embodiments, the element 50 provides a disposable andreplaceable interface between the therapy apparatus 10 and the patient'sscalp 30. By using pre-sterilized and pre-packaged replaceableinterfaces, certain embodiments can advantageously provide sterilizedinterfaces without undergoing cleaning or sterilization processingimmediately before use.

In certain embodiments, the element 50 comprises a container (e.g., acavity or bag) containing a material (e.g., gel or liquid). Thecontainer can be flexible and adapted to conform to the contours of thescalp 30. Other example materials contained in the container of theelement 50 include, but are not limited to, thermal exchange materialssuch as glycerol and water. The element 50 of certain embodimentssubstantially covers the entire scalp 30 of the patient, asschematically illustrated in FIG. 2. In other embodiments, the element50 only covers a localized portion of the scalp 30 in proximity to theirradiated portion of the scalp 30.

In certain embodiments, at least a portion of the element 50 is withinan optical path of the light from the light source 40 to the scalp 30.In such embodiments, the element 50 is substantially opticallytransmissive at a wavelength of the light emitted by the output emissionarea 41 of the light source 40 and is adapted to reduce back reflectionsof the light. By reducing back reflections, the element 50 increases theamount of light transmitted to the brain 20 and reduces the need to usea higher power light source 40 which may otherwise create temperatureincreases at the scalp 30. In certain such embodiments, the element 50comprises one or more optical coatings, films, layers, membranes, etc.in the optical path of the transmitted light which are adapted to reduceback reflections.

In certain such embodiments, the element 50 reduces back reflections byfitting to the scalp 30 so as to substantially reduce air gaps betweenthe scalp 30 and the element 50 in the optical path of the light. Therefractive-index mismatches between such an air gap and the element 50and/or the scalp 30 would otherwise result in at least a portion of thelight propagating from the light source 40 to the brain 20 to bereflected back towards the light source 40.

In addition, certain embodiments of the element 50 comprise a materialhaving, at a wavelength of light emitted by the light source 40, arefractive index which substantially matches the refractive index of thescalp 30 (e.g., about 1.3), thereby reducing anyindex-mismatch-generated back reflections between the element 50 and thescalp 30. Examples of materials with refractive indices compatible withembodiments described herein include, but are not limited to, glycerol,water, and silica gels. Example index-matching gels include, but are notlimited to, those available from Nye Lubricants, Inc. of Fairhaven,Mass.

In certain embodiments, the element 50 is adapted to cool the scalp 30by removing heat from the scalp 30 so as to inhibit temperatureincreases at the scalp 30. In certain such embodiments, the element 50comprises a reservoir (e.g., a chamber or a conduit) adapted to containa coolant. The coolant flows through the reservoir near the scalp 30.The scalp 30 heats the coolant, which flows away from the scalp 30,thereby removing heat from the scalp 30 by active cooling. The coolantin certain embodiments circulates between the element 50 and a heattransfer device, such as a chiller, whereby the coolant is heated by thescalp 30 and is cooled by the heat transfer device. Example materialsfor the coolant include, but are not limited to, water or air.

In certain embodiments, the element 50 comprises a container 51 (e.g., aflexible bag) coupled to an inlet conduit 52 and an outlet conduit 53,as schematically illustrated in FIG. 3. A flowing material (e.g., water,air, or glycerol) can flow into the container 51 from the inlet conduit52, absorb heat from the scalp 30, and flow out of the container 51through the outlet conduit 53. Certain such embodiments can provide amechanical fit of the container 51 to the scalp 30 and sufficientthermal coupling to prevent excessive heating of the scalp 30 by thelight. In certain embodiments, the container 51 can be disposable andreplacement containers 51 can be used for subsequent patients.

In still other embodiments, the element 50 comprises a container (e.g.,a flexible bag) containing a material which does not flow out of thecontainer but is thermally coupled to the scalp 30 so as to remove heatfrom the scalp 30 by passive cooling. Example materials include, but arenot limited to, water, glycerol, and gel. In certain such embodiments,the non-flowing material can be pre-cooled (e.g., by placement in arefrigerator) prior to the phototherapy treatment to facilitate coolingof the scalp 30.

In certain embodiments, the element 50 is adapted to apply pressure toat least a portion of the scalp 30. By applying sufficient pressure, theelement 50 can blanch the portion of the scalp 30 by forcing at leastsome blood out the optical path of the light energy. The blood removalresulting from the pressure applied by the element 50 to the scalp 30decreases the corresponding absorption of the light energy by blood inthe scalp 30. As a result, temperature increases due to absorption ofthe light energy by blood at the scalp 30 are reduced. As a furtherresult, the fraction of the light energy transmitted to the subdermaltarget tissue of the brain 20 is increased. In certain embodiments, apressure greater than two pounds per square inch is used to blanch theirradiated portion of the scalp 30, while in certain other embodiments,a pressure of at least one pound per square inch is used to blanch theirradiated portion of the scalp 30. Other ranges of pressures forblanching the irradiated portion of the scalp 30 are also compatiblewith certain embodiments described herein. The maximum pressure used toblanch the irradiated portion of the scalp 30 is limited in certainembodiments by patient comfort levels and tissue damage levels.

FIGS. 4A and 4B schematically illustrate embodiments of the element 50adapted to facilitate the blanching of the scalp 30. In thecross-sectional view of a portion of the therapy apparatus 10schematically illustrated in FIG. 4A, certain element portions 72contact the patient's scalp 30 and other element portions 74 are spacedaway from the scalp 30. The element portions 72 contacting the scalp 30provide an optical path for light to propagate from the light source 40to the scalp 30. The element portions 72 contacting the scalp 30 alsoapply pressure to the scalp 30, thereby forcing blood out from beneaththe element portion 72. FIG. 4B schematically illustrates a similar viewof an embodiment in which the light source 40 comprises a plurality oflight sources 40 a, 40 b, 40 c.

FIG. 5A schematically illustrates one embodiment of the cross-sectionalong the line 4-4 of FIG. 4B. The element portions 72 contacting thescalp 30 comprise ridges extending along one direction, and the elementportions 74 spaced away from the scalp 30 comprise troughs extendingalong the same direction. In certain embodiments, the ridges aresubstantially parallel to one another and the troughs are substantiallyparallel to one another. FIG. 5B schematically illustrates anotherembodiment of the cross-section along the line 4-4 of FIG. 4B. Theelement portions 72 contacting the scalp 30 comprise a plurality ofprojections in the form of a grid or array. More specifically, theportions 72 are rectangular and are separated by element portions 74spaced away from the scalp 30, which form troughs extending in twosubstantially perpendicular directions. The portions 72 of the element50 contacting the scalp 30 can be a substantial fraction of the totalarea of the element 50 or of the scalp 30.

FIGS. 6A-6C schematically illustrate an embodiment in which the lightsources 40 are spaced away from the scalp 30. In certain suchembodiments, the light emitted by the light sources 40 propagates fromthe light sources 40 through the scalp 30 to the brain 20 and dispersesin a direction generally parallel to the scalp 30, as shown in FIG. 6A.The light sources 40 are preferably spaced sufficiently far apart fromone another such that the light emitted from each light source 40overlaps with the light emitted from the neighboring light sources 40 atthe brain 20. FIG. 6B schematically illustrates this overlap as theoverlap of circular spots 42 at a reference depth at or below thesurface of the brain 20. FIG. 6C schematically illustrates this overlapas a graph of the power density at the reference depth of the brain 20along the line L-L of FIGS. 6A and 6B. Summing the power densities fromthe neighboring light sources 40 (shown as a dashed line in FIG. 6C)serves to provide a more uniform light distribution at the tissue to betreated. In such embodiments, the summed power density is preferablyless than a damage threshold of the brain 20 and above an efficacythreshold.

In certain embodiments, the element 50 is adapted to diffuse the lightprior to reaching the scalp 30. FIGS. 7A and 7B schematically illustratethe diffusive effect on the light by the element 50. An example energydensity profile of the light emitted by a light source 40, asillustrated by FIG. 7A, is peaked at a particular emission angle. Afterbeing diffused by the element 50, as illustrated by FIG. 7B, the energydensity profile of the light does not have a substantial peak at anyparticular emission angle, but is substantially evenly distributed amonga range of emission angles. By diffusing the light emitted by the lightsource 40, the element 50 distributes the light energy substantiallyevenly over the area to be illuminated, thereby inhibiting “hot spots”which would otherwise create temperature increases at the scalp 30. Inaddition, by diffusing the light prior to its reaching the scalp 30, theelement 50 can effectively increase the spot size of the light impingingthe scalp 30, thereby advantageously lowering the power density at thescalp 30, as described more fully below. In addition, in embodimentswith multiple light sources 40, the element 50 can diffuse the light toalter the total light output distribution to reduce inhomogeneities.

In certain embodiments, the element 50 provides sufficient diffusion ofthe light such that the power density of the light is less than amaximum tolerable level of the scalp 30 and brain 20. In certain otherembodiments, the element 50 provides sufficient diffusion of the lightsuch that the power density of the light equals a therapeutic value atthe target tissue. The element 50 can comprise example diffusersincluding, but are not limited to, holographic diffusers such as thoseavailable from Physical Optics Corp. of Torrance, Calif. and DisplayOptics P/N SN1333 from Reflexite Corp. of Avon, Conn.

Power Density

Phototherapy for the treatment of neurologic conditions (e.g.,neurodegenerative diseases such as Parkinson's disease) is based in parton the concept that power density (i.e., power per unit area or numberof photons per unit area per unit time) and energy density (i.e., energyper unit area or number of photons per unit area) of the light energyapplied to tissue appear to be significant factors in determining therelative efficacy of low level phototherapy. Certain embodimentsdescribed herein are based at least in part on the concept that, given aselected wavelength of light energy, it is the power density and/or theenergy density of the light delivered to tissue (as opposed to the totalpower or total energy delivered to the tissue) that are importantfactors in determining the relative efficacy of phototherapy.

The significance of the power density used in phototherapy hasramifications with regard to the devices and methods used inphototherapy of brain tissue, as schematically illustrated by FIGS. 8Aand 8B, which show the effects of scattering by intervening tissue.Further information regarding the scattering of light by tissue isprovided by V. Tuchin in “Tissue Optics: Light Scattering Methods andInstruments for Medical Diagnosis,” SPIE Press (2000), Bellingham,Wash., pp. 3-11, which is incorporated in its entirety by referenceherein.

FIG. 8A schematically illustrates a light beam 80 impinging a portion 90of a patient's scalp 30 and propagating through the patient's head toirradiate a portion 100 of the patient's brain tissue 20. In the exampleembodiment of FIG. 8A, the light beam 80 impinging the scalp 30 iscollimated and has a circular cross-section with a radius of 2 cm and across-sectional area of approximately 12.5 cm². For comparison purposes,FIG. 8B schematically illustrates a light beam 82 having a significantlysmaller cross-section impinging a smaller portion 92 of the scalp 30 toirradiate a portion 102 of the brain tissue 20. The light beam 82impinging the scalp 30 in FIG. 8B is collimated and has a circularcross-section with a radius of 1 cm and a cross-sectional area ofapproximately 3.1 cm². The collimations, cross-sections, and radii ofthe light beams 80, 82 illustrated in FIGS. 8A and 8B are examples;other light beams with other parameters are also compatible withembodiments described herein. In particular, similar considerationsapply to focused beams or diverging beams, as they are similarlyscattered by the intervening tissue.

As shown in FIGS. 8A and 8B, the cross-sections of the light beams 80,82 become larger while propagating through the head due to scatteringfrom interactions with tissue of the head. Assuming that the angle ofdispersion is 15 degrees and the irradiated brain tissue 20 is 2.5 cmbelow the scalp 30, the resulting area of the portion 100 of braintissue 20 irradiated by the light beam 80 in FIG. 8A is approximately22.4 cm². Similarly, the resulting area of the portion 102 of braintissue 20 irradiated by the light beam 82 in FIG. 8B is approximately8.8 cm².

Irradiating the portion 100 of the brain tissue 20 with a power densityof 10 mW/cm² corresponds to a total power within the portion 100 ofapproximately 224 mW (10 mW/cm²×22.4 cm²). Assuming only approximately5% of the light beam 80 is transmitted between the scalp 30 and thebrain tissue 20, the incident light beam 80 at the scalp 30 will have atotal power of approximately 4480 mW (224 mW/0.05) and a power densityof approximately 358 mW/cm² (4480 mW/12.5 cm²). Similarly, irradiatingthe portion 102 of the brain tissue 20 with a power density of 10 mW/cm²corresponds to a total power within the portion 102 of approximately 88mW (10 mW/cm²×8.8 cm²), and with the same 5% transmittance, the incidentlight beam 82 at the scalp 30 will have a total power of approximately1760 mW (88 mW/0.05) and a power density of approximately 568 mW/cm²(1760 mW/3.1 cm²). These calculations are summarized in Table 1.

TABLE 1 2 cm Spot Size 1 cm Spot Size (FIG. 8A) (FIG. 8B) Scalp: Area12.5 cm² 3.1 cm² Total power 4480 mW 1760 mW Power density 358 mW/cm²568 mW/cm² Brain: Area 22.4 cm² 8.8 cm² Total power 224 mW 88 mW Powerdensity 10 mW/cm² 10 mW/cm²

These example calculations illustrate that to obtain a desired powerdensity at the brain 20, higher total power at the scalp 30 can be usedin conjunction with a larger spot size at the scalp 30. Thus, byincreasing the spot size at the scalp 30, a desired power density at thebrain 20 can be achieved with lower power densities at the scalp 30which can reduce the possibility of overheating the scalp 30. In certainembodiments, the light can be directed through an aperture to define theillumination of the scalp 30 to a selected smaller area.

Light Source

In certain embodiments, a single light source 40 is used as a lightgenerator to generate light, while in other embodiments, a plurality oflight sources 40 are used as a light generator to generate light. Thelight source 40 preferably generates light in the visible tonear-infrared wavelength range. In certain embodiments, the light source40 comprises one or more laser diodes, which each provide coherentlight. In embodiments in which the light from the light source 40 iscoherent, the emitted light may produce “speckling” due to coherentinterference of the light. This speckling comprises intensity spikeswhich are created by constructive interference and can occur inproximity to the target tissue being treated. For example, while theaverage power density may be approximately 10 mW/cm², the power densityof one such intensity spike in proximity to the brain tissue to betreated may be approximately 300 mW/cm². In certain embodiments, thisincreased power density due to speckling can improve the efficacy oftreatments using coherent light over those using incoherent light forillumination of deeper tissues.

In other embodiments, the light source 40 provides incoherent light.Example light sources 40 of incoherent light include, but are notlimited to, incandescent lamps or light-emitting diodes. A heat sink canbe used with the light source 40 (for either coherent or incoherentsources) to remove heat from the light source 40 and to inhibittemperature increases at the scalp 30.

In certain embodiments, the light source 40 generates light which issubstantially monochromatic (i.e., light having one wavelength, or lighthaving a narrow band of wavelengths). So that the amount of lighttransmitted to the brain is maximized, the wavelength of the light isselected in certain embodiments to be at or near a transmission peak (orat or near an absorption minimum) for the intervening tissue. In certainsuch embodiments, the wavelength corresponds to a peak in thetransmission spectrum of tissue at about 820 nanometers. In otherembodiments, the wavelength of the light is preferably between about 630nanometers and about 1064 nanometers, more preferably between about 780nanometers and about 840 nanometers, and most preferably includeswavelengths of about 785, 790, 795, 800, 805, 810, 815, 820, 825, or 830nanometers. An intermediate wavelength in a range between approximately730 nanometers and approximately 750 nanometers (e.g., about 739nanometers) appears to be suitable for penetrating the skull, althoughother wavelengths are also suitable and may be used.

In other embodiments, the light source 40 generates light having aplurality of wavelengths. For example, in certain embodiments, a band ofwavelengths of (808±5) nanometers is used. In certain embodiments, thelight source 40 is adapted to generate light having a first wavelengthconcurrently with light having a second wavelength. In certain otherembodiments, the light source 40 is adapted to generate light having afirst wavelength sequentially with light having a second wavelength.

In certain such embodiments, each wavelength is selected so as to workwith one or more chromophores within the target tissue. Without beingbound by theory or by a specific mechanism, it is believed thatirradiation of chromophores increases the production of ATP in thetarget tissue, thereby producing beneficial effects, as described morefully below.

In certain embodiments, the light source 40 includes at least onecontinuously emitting GaAlAs laser diode having a wavelength of about830 nanometers. In another embodiment, the light source 40 comprises alaser source having a wavelength of about 808 nanometers. In still otherembodiments, the light source 40 includes at least one vertical cavitysurface-emitting laser (VCSEL) diode. Other light sources 40 compatiblewith embodiments described herein include, but are not limited to,light-emitting diodes (LEDs) and filtered lamps.

The light source 40 is capable of emitting light energy at a powersufficient to achieve a predetermined power density at the subdermaltarget tissue (e.g., at a depth of approximately 2 centimeters from thedura). It is presently believed that phototherapy of tissue is mosteffective when irradiating the target tissue with power densities oflight of at least about 0.01 mW/cm² and up to about 1 W/cm² at the levelof the tissue. In various embodiments, the subsurface power density isat least about 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 30, 40, 50, 60,70, 80, or 90 mW/cm², respectively, depending on the desired clinicalperformance. In certain embodiments, the subsurface power density at thetarget tissue is about 0.01 mW/cm² to about 100 mW/cm², about 0.01mW/cm² to about 50 mW/cm², about 2 mW/cm² to about 20 mW/cm², or about 5mW/cm² to about 25 mW/cm². It is believed that these subsurface powerdensities are especially effective at producing the desiredbiostimulative effects on the tissue being treated.

Taking into account the attenuation of energy as it propagates from theskin surface, through body tissue, bone, and fluids, to the subdermaltarget tissue, surface power densities preferably between about 10mW/cm² to about 10 W/cm², or more preferably between about 100 mW/cm² toabout 500 mW/cm², will typically be used to attain the selected powerdensities at the subdermal target tissue. To achieve such surface powerdensities, the light source 40 is preferably capable of emitting lightenergy having a total power output of at least about 25 mW to about 100W. In various embodiments, the total power output is limited to be nomore than about 30, 50, 75, 100, 150, 200, 250, 300, 400, or 500 mW,respectively. In certain embodiments, the light source 40 comprises aplurality of sources used in combination to provide the total poweroutput. The actual power output of the light source 40 is preferablycontrollably variable. In this way, the power of the light energyemitted can be adjusted in accordance with a selected power density atthe subdermal tissue being treated.

Certain embodiments utilize a light source 40 that includes only asingle laser diode that is capable of providing about 25 mW to about 100W of total power output at the skin surface. In certain suchembodiments, the laser diode can be optically coupled to the scalp 30via an optical fiber or can be configured to provide a sufficientlylarge spot size to avoid power densities which would burn or otherwisedamage the scalp 30. In other embodiments, the light source 40 utilizesa plurality of sources (e.g., laser diodes) arranged in a grid or arraythat together are capable of providing at least about 25 mW to about 100W of total power output at the skin surface. The light source 40 ofother embodiments may also comprise sources having power capacitiesoutside of these limits.

FIG. 9A schematically illustrates another embodiment of the therapyapparatus 10 which comprises the cap 60 and a light source comprising alight-emitting blanket 110. FIG. 9B schematically illustrates anembodiment of the blanket 110 comprising a flexible substrate 111 (e.g.,flexible circuit board), a power conduit interface 112, and a sheetformed by optical fibers 114 positioned in a fan-like configuration.FIG. 9C schematically illustrates an embodiment of the blanket 110comprising a flexible substrate 111, a power conduit interface 112, anda sheet formed by optical fibers 114 woven into a mesh. The blanket 110is preferably positioned within the cap 60 so as to cover an area of thescalp 30 corresponding to a portion of the brain 20 to be treated.

In certain such embodiments, the power conduit interface 112 is adaptedto be coupled to an optical fiber conduit 64 which provides opticalpower to the blanket 110. The optical power interface 112 of certainembodiments comprises a beam splitter or other optical device whichdistributes the incoming optical power among the various optical fibers114. In other embodiments, the power conduit interface 112 is adapted tobe coupled to an electrical conduit which provides electrical power tothe blanket 110. In certain such embodiments, the power conduitinterface 112 comprises one or more laser diodes, the output of which isdistributed among the various optical fibers 114 of the blanket 110. Incertain other embodiments, the blanket 110 comprises anelectroluminescent sheet which responds to electrical signals from thepower conduit interface 112 by emitting light. In such embodiments, thepower conduit interface 112 comprises circuitry adapted to distributethe electrical signals to appropriate portions of the electroluminescentsheet.

The side of the blanket 110 nearer the scalp 30 is preferably providedwith a light scattering surface, such as a roughened surface to increasethe amount of light scattered out of the blanket 110 towards the scalp30. The side of the blanket 110 further from the scalp 30 is preferablycovered by a reflective coating so that light emitted away from thescalp 30 is reflected back towards the scalp 30. This configuration issimilar to configurations used for the “back illumination” ofliquid-crystal displays (LCDs). Other configurations of the blanket 110are compatible with embodiments described herein.

In certain embodiments, the light source 40 generates light which causeeye damage if viewed by an individual. In such embodiments, theapparatus 50 can be configured to provide eye protection so as to avoidviewing of the light by individuals. For example, opaque materials canbe appropriately placed to block the light from being viewed directly.In addition, interlocks can be provided so that the light source 40 isnot activated unless the apparatus 50 is in place, or other appropriatesafety measures are taken.

Light Delivery Apparatuses

The phototherapy methods for the treatments described herein may bepracticed and described using, for example, a low level laser therapyapparatus such as that shown and described in U.S. Pat. No. 6,214,035,U.S. Pat. No. 6,267,780, U.S. Pat. No. 6,273,905 and U.S. Pat. No.6,290,714, which are all incorporated in their entirety by referenceherein, as are the references incorporated by reference therein.

Another suitable phototherapy apparatus in accordance with embodimentsdescribed here is illustrated in FIG. 10. The illustrated therapyapparatus 10 includes a light source 40, an element 50, and a flexiblestrap 120 adapted for securing the therapy apparatus 10 over an area ofthe patient's head. The light source 40 can be disposed on the strap 120itself, or in a housing 122 coupled to the strap 120. The light source40 preferably comprises a plurality of diodes 40 a, 40 b, etc. capableof emitting light energy having a wavelength in the visible tonear-infrared wavelength range. The element 50 is adapted to bepositioned between the light source 40 and the patient's scalp 30.

The therapy apparatus 10 further includes a power supply (not shown)operatively coupled to the light source 40, and a programmablecontroller 126 operatively coupled to the light source 40 and to thepower supply. The programmable controller 126 is configured to controlthe light source 40 so as to deliver a predetermined power density tothe brain tissue 20. In certain embodiments, as schematicallyillustrated in FIG. 10, the light source 40 comprises the programmablecontroller 126. In other embodiments the programmable controller 126 isa separate component of the therapy apparatus 10.

In certain embodiments, the strap 120 comprises a loop of elastomericmaterial sized appropriately to fit snugly onto the patient's scalp 30.In other embodiments, the strap 120 comprises an elastomeric material towhich is secured any suitable securing means 130, such as mating Velcrostrips, buckles, snaps, hooks, buttons, ties, or the like. The preciseconfiguration of the strap 120 is subject only to the limitation thatthe strap 120 is capable of maintaining the light source 40 in aselected position so that light energy emitted by the light source 40 isdirected towards the targeted brain tissue 20.

In the example embodiment illustrated in FIG. 10, the housing 122comprises a layer of flexible plastic or fabric that is secured to thestrap 120. In other embodiments, the housing 122 comprises a plate or anenlarged portion of the strap 120. Various strap configurations andspatial distributions of the light sources 40 are compatible withembodiments described herein so that the therapy apparatus 10 can treatselected portions of brain tissue.

In still other embodiments, the therapy apparatus 10 for delivering thelight energy includes a handheld probe 140, as schematically illustratedin FIG. 11. The probe 140 includes a light source 40 and an element 50as described herein.

FIG. 12 is a block diagram of a control circuit 200 comprising aprogrammable controller 126 according to embodiments described herein.The control circuit 200 is configured to adjust the power of the lightenergy emitted by the light source 40 to generate a predeterminedsurface power density at the scalp 30 corresponding to a predeterminedenergy delivery profile, such as a predetermined subsurface powerdensity, to the target area of the brain 20.

In certain embodiments, the programmable controller 126 comprises alogic circuit 210, a clock 212 coupled to the logic circuit 210, and aninterface 214 coupled to the logic circuit 210. The clock 212 of certainembodiments provides a timing signal to the logic circuit 210 so thatthe logic circuit 210 can monitor and control timing intervals of theapplied light. Examples of timing intervals include, but are not limitedto, total treatment times, pulsewidth times for pulses of applied light,and time intervals between pulses of applied light. In certainembodiments, the light sources 40 can be selectively turned on and offto reduce the thermal load on the scalp 30 and to deliver a selectedpower density to particular areas of the brain 20.

The interface 214 of certain embodiments provides signals to the logiccircuit 210 which the logic circuit 210 uses to control the appliedlight. The interface 214 can comprise a user interface or an interfaceto a sensor monitoring at least one parameter of the treatment. Incertain such embodiments, the programmable controller 126 is responsiveto signals from the sensor to preferably adjust the treatment parametersto optimize the measured response. The programmable controller 126 canthus provide closed-loop monitoring and adjustment of various treatmentparameters to optimize the phototherapy. The signals provided by theinterface 214 from a user are indicative of parameters that may include,but are not limited to, patient characteristics (e.g., skin type, fatpercentage), selected applied power densities, target time intervals,and power density/timing profiles for the applied light.

In certain embodiments, the logic circuit 210 is coupled to a lightsource driver 220. The light source driver 220 is coupled to a powersupply 230, which in certain embodiments comprises a battery and inother embodiments comprises an alternating current source. The lightsource driver 220 is also coupled to the light source 40. The logiccircuit 210 is responsive to the signal from the clock 212 and to userinput from the user interface 214 to transmit a control signal to thelight source driver 220. In response to the control signal from thelogic circuit 210, the light source driver 220 adjust and controls thepower applied to the light sources 40. Other control circuits besidesthe control circuit 200 of FIG. 12 are compatible with embodimentsdescribed herein.

In certain embodiments, the logic circuit 110 is responsive to signalsfrom a sensor monitoring at least one parameter of the treatment tocontrol the applied light. For example, certain embodiments comprise atemperature sensor thermally coupled to the scalp 30 to provideinformation regarding the temperature of the scalp 30 to the logiccircuit 210. In such embodiments, the logic circuit 210 is responsive tothe information from the temperature sensor to transmit a control signalto the light source driver 220 so as to adjust the parameters of theapplied light to maintain the scalp temperature below a predeterminedlevel. Other embodiments include example biomedical sensors including,but not limited to, a blood flow sensor, a blood gas (e.g., oxygenation)sensor, an ATP production sensor, or a cellular activity sensor. Suchbiomedical sensors can provide real-time feedback information to thelogic circuit 210. In certain such embodiments, the logic circuit 110 isresponsive to signals from the sensors to preferably adjust theparameters of the applied light to optimize the measured response. Thelogic circuit 110 can thus provide closed-loop monitoring and adjustmentof various parameters of the applied light to optimize the phototherapy.

In certain embodiments, as schematically illustrated in FIG. 13, thetherapy apparatus 310 comprises a light source 340 adapted to irradiatea portion of the patient's brain 20 with an efficacious power densityand wavelength of light. The therapy apparatus 310 further comprises acontroller 360 for energizing said light source 340, so as toselectively produce a plurality of different irradiation patterns on thepatient's scalp 30. Each of the irradiation patterns is comprised of aleast one illuminated area that is small compared to the patient's scalp30, and at least one non-illuminated area.

In certain embodiments, the light source 340 includes an apparatus foradjusting the emitted light to irradiate different portions of the scalp30. In certain such embodiments, the apparatus physically moves thelight source 40 relative to the scalp 30. In other embodiments, theapparatus does not move the light source 40, but redirects the emittedlight to different portions of the scalp 30. In an example embodiment,as schematically illustrated in FIG. 14, the light source 340 comprisesa laser diode 342 and a galvometer 344, both of which are electricallycoupled to the controller 360. The galvometer 344 comprises a mirror 346mounted onto an assembly 348 which is adjustable by a plurality ofmotors 350. Light emitted by the laser diode 342 is directed toward themirror 346 and is reflected to selected portions of the patient's scalp30 by selectively moving the mirror 346 and selectively activating thelaser diode 342. In certain embodiments, the therapy apparatus 310comprises an element 50 adapted to inhibit temperature increases at thescalp 30 as described herein.

FIG. 15A schematically illustrates an irradiation pattern 370 inaccordance with embodiments described herein. The irradiation pattern370 comprises at least one illuminated area 372 and at least onenon-illuminated area 374. In certain embodiments, the irradiationpattern 370 is generated by scanning the mirror 346 so that the lightimpinges the patient's scalp 30 in the illuminated area 372 but not inthe non-illuminated area 374. Certain embodiments modify the illuminatedarea 372 and the non-illuminated area 374 as a function of time.

This selective irradiation can be used to reduce the thermal load onparticular locations of the scalp 30 by moving the light from oneilluminated area 372 to another. For example, by irradiating the scalp30 with the irradiation pattern 370 schematically illustrated in FIG.15A, the illuminated areas 372 of the scalp 30 are heated by interactionwith the light, and the non-illuminated areas 374 are not heated. Bysubsequently irradiating the scalp 30 with the complementary irradiationpattern 370′ schematically illustrated in FIG. 15B, the previouslynon-illuminated areas 374 are now illuminated areas 372′, and thepreviously illuminated areas 372 are now non-illuminated areas 374′. Acomparison of the illuminated areas 372 of the irradiation pattern 370of FIG. 15A with the illuminated area 372′ of the irradiation pattern370′ of FIG. 15B shows that the illuminated areas 372, 372′ do notsignificantly overlap one another. In this way, the thermal load at thescalp 30 due to the absorption of the light can be distributed acrossthe scalp 30, thereby avoiding unduly heating one or more portions ofthe scalp 30.

FIG. 16 schematically illustrates another therapy apparatus 400 inaccordance with embodiments described herein. The therapy apparatus 400comprises a plurality of light sources 410 in a housing 420. Each lightsource 410 has an output emission area positioned to irradiate acorresponding portion of the brain 20 with an efficacious power densityand wavelength of light. In certain embodiments, these portions overlapsuch that the portion of the brain 20 irradiated by two or more lightsources 410 overlap one another at least in part. As described herein,the light sources 410 can be activated by a controller (not shown) inconcert or separately to produce a predetermined irradiation pattern.

The therapy apparatus 400 of FIG. 16 further comprises a cap 430interposed between the light sources 410 and the patient's scalp 30,such that light passes through the cap 430 prior to reaching the scalp30. In certain embodiments, the cap 430 is substantially opticallytransmissive at the wavelength and reduces back reflections of thelight. The cap 430 of certain embodiments fits to the scalp 30 so as tosubstantially reduce air gaps between the scalp 30 and the cap 430. Incertain embodiments, the cap 430 comprises a material having arefractive index which substantially matches a refractive index of thescalp 30. In certain embodiments, the cap 430 comprises a materialhaving a refractive index which substantially matches a refractive indexof the skin and/or hair of the scalp 30.

In the embodiment schematically illustrated by FIG. 16, the cap 430 iswearable over the patient's scalp 30. In certain such embodiments, thepatient wears the cap 430 and is in a reclining position so as to placehis head in proximity to the light sources 410. The cap 430 is adaptedto inhibit temperature increases at the scalp 30 caused by the lightfrom the light sources 410, as described herein (e.g., by cooling thescalp 30, by blanching a portion of the scalp 30, by diffusing the lightprior to reaching the scalp 30).

Example Wearable Apparatus

FIG. 19 schematically illustrates an example apparatus 500 which iswearable by a patient for treating the patient's brain. The apparatus500 comprises a body 510 and a plurality of elements 520. The body 510covers at least a portion of the patient's scalp when the apparatus 500is worn by the patient. Each element 520 has a first portion 522 whichconforms to a corresponding portion of the patient's scalp when theapparatus 500 is worn by the patient. Each element 520 has a secondportion 524 which conforms to a light source (not shown in FIG. 19)removably contacting the element. Each element 520 is substantiallytransmissive (e.g., substantially transparent or substantiallytranslucent) to light from the light source to irradiate at least aportion of the patient's brain. In certain embodiments, the light fromthe light source after being transmitted through each element 520 has apower density which penetrates the patient's cranium to deliver anefficacious amount of light to at least a portion of the patient'sbrain.

FIG. 20 schematically illustrates an example apparatus 500 having aplurality of elements 520 in accordance with certain embodimentsdescribed herein. The body 510 shown in FIG. 20 has a plurality ofapertures 512 or openings which serve as indicators of treatment sitelocations. Each element 520 is positioned at a corresponding one of theplurality of apertures 512 and serves as an optical window. In certainembodiments, the plurality of elements 520 comprises at least about 10elements 520, while in certain other embodiments, the plurality ofelements 520 comprises 20 elements 520. In certain other embodiments,the plurality of elements 520 comprises between 15 and 25 elements 520.In certain embodiments in which the light emitting apparatus 600 isconfigured to directly contact the scalp, the apertures 512 of the body510 do not contain any elements 520, but instead are indicators oftreatment site locations through which the light emitting apparatus 600is positioned for treatment.

In certain embodiments, the body 510 comprises a hood, as schematicallyillustrated by FIG. 20, while in other embodiments, the body 510comprises a cap or has another configuration which is wearable on thepatient's head and serves as a support for orienting the elements 520 onthe patient's head. In certain embodiments, the body 510 comprises astretchable material which generally conforms to the patient's scalp. Incertain embodiments, the body 510 comprises nylon-backedpolychloroprene. In certain embodiments, the body 510 is available indifferent sizes (e.g., small, medium, large) to accommodate differentsizes of heads. In certain embodiments, the apparatus 500 is disposableafter a single use to advantageously avoid spreading infection ordisease between subsequent patients.

FIG. 21 schematically illustrates an example element 520 in an explodedview. The example element 520 comprises an optical component 532, afirst support ring 534, a second support ring 536, and a label 538.Other configurations of the element 520 are also compatible with certainembodiments described herein.

In certain embodiments, the optical component 532 comprises asubstantially transmissive (e.g., substantially transparent orsubstantially translucent) bag comprising a flexible material (which canbe biocompatible). FIG. 22A schematically illustrates an example opticalcomponent 532 with example dimensions in inches. The bag of FIG. 22Acomprises an inflatable container which contains a substantiallytransmissive liquid (e.g., water) or gel. In certain embodiments, thebag has an outer diameter within a range between about 0.5 inch andabout 3 inches. For example, the bag of FIG. 22A has an outer diameterof about 1.37 inches. In certain embodiments, the bag has a volume in arange between about 2 cubic centimeters and about 50 cubic centimeters.

Both the bag and the liquid contained within the bag are substantiallytransmissive to light having wavelengths to be applied to the patient'sbrain (e.g., wavelength of approximately 810 nanometers). In certainembodiments, the liquid has a refractive index which substantiallymatches a refractive index of the patient's scalp, therebyadvantageously providing an optical match between the element 520 andthe patient's scalp. While the example optical component 532 of FIG. 22Acomprises a single bag, in certain other embodiments, the opticalcomponent 532 comprises a plurality of bags filled with a substantiallytransparent liquid.

FIGS. 22B and 22C schematically illustrate other example opticalcomponents 532 in which the bag contains a composite material. Forexample, in FIGS. 22B and 22C, the bag contains a first material 523 anda second material 525. In certain embodiments, the first material 523comprises a soft, substantially transmissive, thermally insulativematerial (e.g., gel). Example gels compatible with certain embodimentsdescribed herein include, but are not limited to, OC-431A-LVP, OCK-451,and OC-462 optical gels available from Nye Corporation of Fairhaven,Mass. In certain embodiments, the second material 525 comprises a rigid,substantially transmissive, thermally conductive material (e.g.,silica).

In certain embodiments, as schematically illustrated in FIG. 22B, thesecond material 525 comprises a plurality of balls distributed withinthe first material 523. The balls of certain embodiments have diametersless than about 2 millimeters. In certain other embodiments, asschematically illustrated in FIG. 22C, the first material 523 comprisesa first plurality of layers and the second material 525 comprises asecond plurality of layers. The first plurality of layers is stackedwith the second plurality of layers, thereby forming a stack havingalternating layers of the first material 523 and the second material525. In certain embodiments, each layer of the first plurality of layershas a thickness less than about 2 millimeters and each layer of thesecond plurality of layers has a thickness less than about 2millimeters. In certain other embodiments, each layer of the firstplurality of layers and each layer of the second plurality of layers hasa thickness less than about 0.5 millimeter. Other configurations of thefirst material 523 and the second material 525 within the opticalcomponent 532 are also compatible with certain embodiments describedherein.

The optical component 532 of certain embodiments advantageously deformsin response to pressure applied to the first portion 522 and the secondportion 524. For example, without a load being applied, the opticalcomponent 532 of FIG. 22A has a thickness of approximately 0.41 inch,but with approximately four pounds of applied pressure, the opticalcomponent 532 of FIG. 22A has a thickness of approximately 0.315 inch.The first portion 522 of the optical component 532 advantageouslydeforms to substantially conform to a portion of the patient's skull towhich the optical component 532 is pressed. For example, in certainembodiments, the first portion 522 comprises a conformable surface ofthe optical component 532. Thus, in certain such embodiments, theoptical component 532 advantageously provides an interface with thepatient's scalp which is substantially free of air gaps. The secondportion 524 of the optical component 532 advantageously deforms tosubstantially conform to a light source being pressed thereon. Forexample, in certain embodiments, the second portion 524 comprises aconformable surface of the optical component 532. Thus, in certain suchembodiments, the optical component 532 advantageously provides aninterface with the light source which is substantially free of air gaps.

In certain embodiments, the optical component 532 advantageously servesas a heat sink to inhibit temperature increases at the patient's scalpcaused by light which is transmitted through the optical component 532.In certain such embodiments, the optical component 532 has asufficiently high heat capacity to provide an effective heat sink to thepatient's scalp. For example, for a bag filled with water (which has aheat capacity of approximately 4180 joules/kilogram-K), a generallydisk-shaped bag having a diameter of approximately 32 millimeters and athickness of approximately 10 millimeters has a sufficient volume, and asufficient heat capacity, to provide an effective heat sink. Thus, incertain embodiments, each element 520 advantageously inhibitstemperature increases at the patient's scalp caused by the lighttransmitted through the element 520.

FIG. 23 schematically illustrates an example first support ring 534 withexample dimensions in inches. In certain embodiments, the first supportring 534 comprises a substantially rigid material. Examples ofcompatible materials include, but are not limited to, plastic (e.g.,acrylonitrile butadiene styrene or ABS). As illustrated in FIG. 23, thefirst support ring 534 of certain embodiments is configured to bemounted in a corresponding aperture 512 of the body 510. The examplefirst support ring 534 illustrated in FIG. 23 comprises a generally flatportion 542, an annular portion 544, and one or more protrusions 546configured to connect to the second support ring 536, described morefully below. The generally flat portion 542 has an outer diameter whichis larger than the diameter of the corresponding aperture 512 of thebody 510 and is configured to be mechanically coupled to the body 510(e.g., by adhesive). The annular portion 544 has an outer diameter whichis smaller than or equal to the diameter of the corresponding aperture512 of the body 510 and is configured to fit through the aperture 512.The one or more protrusions 546 extend generally radially from theannular portion 544 such that the overall width of the protrusions 546and the annular portion 544 is larger than the diameter of thecorresponding aperture 512 of the body 510.

FIG. 24 schematically illustrates an example second support ring 536with example dimensions in inches. In certain embodiments, the secondsupport ring 536 comprises a substantially rigid material. Examples ofcompatible materials include, but are not limited to, plastic (e.g.,acrylonitrile butadiene styrene or ABS). As illustrated in FIG. 24, thesecond support ring 536 of certain embodiments is configured to beconnected to the one or more protrusions 546 and the annular portion 544of the first support ring 534. In certain embodiments, the secondsupport ring 536 comprises one or more recesses (not shown) which areconfigured to fit with the one or more protrusions 546 of the firstsupport ring 534. In certain such embodiments, the first support ring534 and the second support ring 536 interlock together to advantageouslyhold the element 520 in place on the body 510. In certain otherembodiments, the first support ring 534 comprises one or more recessesconfigured to mate with one or more corresponding protrusions of thesecond support ring 536.

FIG. 25 schematically illustrates an example label 538 compatible withcertain embodiments described herein. The labels 538 advantageouslyprovide one or more numbers, letters, or symbols (e.g., bar codes) toeach of the elements 520 to distinguish the various elements 520 fromone another. In certain such embodiments, the labels 538 comprise avinyl material and are mechanically coupled to the second support ring536 (e.g., by adhesive) so as to be visible to users of the lighttherapy apparatus. Other types of labels 538 are also compatible withembodiments disclosed herein, including but not limited to, labels 538which are painted or etched onto an outside surface of the secondsupport ring 536.

FIGS. 26A and 26B schematically illustrate the left-side and right-sideof the apparatus 500, respectively, showing an example labelingconfiguration for the apparatus 500. FIG. 26C schematically illustratesthe example labeling configuration of FIGS. 26A and 26B from above aflattened view of the apparatus 500. The labeling convention of FIGS.26A-26C is compatible with irradiation of both halves of the patient'sbrain. Other labeling conventions are also compatible with embodimentsdescribed herein.

In certain embodiments, the labels 538 are advantageously used to guidean operator to irradiate the patient's brain at the various treatmentsites sequentially at each of the treatment sites one at a time throughthe elements 520 in a predetermined order using a light source which canbe optically coupled to sequential elements 520. For example, for thelabeling configuration of FIGS. 26A-26C, the operator can firstirradiate element “1,” followed by elements “2,” “3,”, “4,” etc. tosequentially irradiate each of the twenty treatment sites one at a time.In certain such embodiments, the order of the elements 520 is selectedto advantageously reduce temperature increases which would result fromsequentially irradiating elements 520 in proximity to one another.

In certain embodiments, the labels 538 are advantageously used to keeptrack of which elements 520 have been irradiated and which elements 520are yet to be irradiated. In certain such embodiments, at least aportion of each label 538 (e.g., a pull-off tab) is configured to beremoved from the apparatus 500 when the corresponding element 520 hasbeen irradiated. In certain embodiments, the label 538 has a codesequence which the operator enters into the controller prior toirradiation so as to inform the controller of which element 520 is nextto be irradiated. In certain other embodiments, each label 538 comprisesa bar code or a radio-frequency identification device (RFID) which isreadable by a sensor electrically coupled to the controller. Thecontroller of such embodiments keeps track of which elements 520 havebeen irradiated, and in certain such embodiments, the controller onlyactuates the light source when the light source is optically coupled tothe proper element 520.

FIGS. 27A-27E schematically illustrate various stages of structuresformed during the fabrication of the apparatus 500 of FIGS. 20-25. FIG.27A schematically illustrates the body 510 mounted on a mannequin headfixture 560. The body 510 is mounted in an inside-out configuration andis shown in FIG. 27A after each of the apertures 512 has been cut in thebody 510. In each of the apertures 512, a first support ring 534 isconnected to the body 510, as shown in FIG. 27B. In certain embodiments,a layer of adhesive (e.g., CA40 Scotch-Weld™ instant adhesive availablefrom 3M Company of Saint Paul, Minn.) is applied to a surface of theflat portion 542 which is then pressed onto the body 510 with theannular portion 544 extending through the aperture 512. FIG. 27Cschematically illustrates the optical components 532 mounted on each ofthe first support rings 534. In certain embodiments, a layer of adhesive(e.g., Loctite® 3105 ultraviolet-cured adhesive available from HenkelCorporation of Rocky Hill, Conn.) is applied to a surface of the flatportion 542 which is then pressed together with a corresponding surfaceof the optical component 532 and the adhesive is cured by application ofultraviolet light. FIG. 27D schematically illustrates the body 510 afterbeing removed from the mannequin head fixture 560 and returned to anright-side-out configuration. FIG. 27E schematically illustrates theapparatus 500 after the second support rings 536 have been mounted tothe first support rings 534 and the labels 538 have been applied to thesecond support rings 536.

Example Light Emitting Apparatus

FIG. 28 schematically illustrates an apparatus 600 which emits light forirradiating a patient's skin to treat portions of a patient's bodyunderneath the patient's skin. The apparatus 600 comprises a source 610of light having a wavelength which is substantially transmitted by thepatient's skin. The apparatus 600 further comprises an optical conduit620 optically coupled to the source 610. The apparatus 600 furthercomprises an optical device 630 optically coupled to the optical conduit620. The optical device 630 comprises an optical diffuser 640 opticallycoupled to the optical conduit 620. The optical device 630 furthercomprises an output optical element 650 comprising a rigid andsubstantially thermally conductive material. The output optical element650 is optically coupled to the optical conduit 620 (e.g., via theoptical diffuser 640). A portion of the light transmitted through thepatient's skin irradiates at least a portion of the patient's bodyunderneath the patient's skin with an efficacious power density oflight.

In certain embodiments, the source 610 comprises a laser which emitslight having at least one wavelength in a range between about 630nanometers and about 1064 nanometers. The laser of certain otherembodiments emits light having at least one wavelength in a rangebetween about 780 nanometers and about 840 nanometers. In certainembodiments, the laser emits light having a center wavelength ofapproximately 808 nanometers. The laser of certain embodiments iscapable of generating up to approximately 6 watts of laser light and hasa numerical aperture of approximately 0.16.

FIG. 29 schematically illustrates an example optical conduit 620optically coupled to an example optical device 630. In certainembodiments, the optical conduit 620 comprises an optical fiber 622 anda protective sheath 624 around the optical fiber. The optical fiber 622of certain embodiments is a step-index optical fiber having a numericalaperture of approximately 0.22 (e.g., a 1-millimeter diameter multimodefiber). In certain embodiments, the optical conduit 620 furthercomprises an electrically conductive conduit to transmit signals betweenthe optical device 630 and the source 610 (e.g., from trigger switchesor temperature sensors within the optical device 630) and/or to provideelectrical power to the optical device 630 (e.g., for a thermoelectriccooler).

In certain embodiments, the protective sheath 624 comprises a strainrelief apparatus 625 and a SMA connector 627 which mechanically couplesto a corresponding adjustable SMA mount 631 of the optical device 630.The protective sheath 624 of certain embodiments has a plurality ofrigid segments, with each segment having a generally cylindrical tubularshape and a longitudinal axis. Each segment is articulately coupled toneighboring segments such that an angle between the longitudinal axes ofneighboring segments is limited to be less than a predetermined angle.In certain embodiments, the protective sheath 624 allows the opticalconduit 620 to be moved and to bend, but advantageously limits theradius of curvature of the bend to be sufficiently large to avoidbreaking the optical fiber 622 therein.

The example optical device 630 schematically illustrated by FIG. 29comprises an optical diffuser 640 and an output optical element 650(e.g., a lens). In certain embodiments, the output optical element 650comprises glass (e.g., BK7 glass) which is substantially opticallytransmissive at wavelengths which are substantially transmitted by skin,but is not substantially thermally conductive. In certain otherembodiments, the output optical element 650 is rigid, substantiallyoptically transmissive at wavelengths which are substantiallytransmitted by skin, and substantially thermally conductive.

In certain embodiments, the output optical element 650 has a frontsurface facing generally towards the patient's scalp and a back surfacefacing generally away from the patient's scalp. In certain embodiments,the front surface is adapted to be placed in contact with either theskin or with an intervening material in contact with the skin duringirradiation. In certain such embodiments, the thermal conductivity ofthe output optical element 650 is sufficient to allow heat to flow fromthe front surface of the output optical element 650 to a heat sink inthermal communication with the back surface of the output opticalelement 650. In certain embodiments, the output optical element 650conducts heat from the front surface to the back surface at a sufficientrate to prevent, minimize, or reduce damage to the skin or discomfort tothe patient from excessive heating of the skin due to the irradiation.

The existence of air gaps between the output optical element 650 and thescalp can create a problem in controlling the heating of the skin by theirradiation. In certain embodiments, the output optical element 650 isplaced in contact with the skin of the scalp so as to advantageouslyavoid creating air gaps between the output optical element 650 and theskin. In certain other embodiments in which an intervening material isin contact with the skin and with the output optical element 650, theoutput optical element 650 is placed in contact with the interveningmaterial so as to advantageously avoid creating air gaps between theoutput optical element 650 and the intervening material or between theintervening material and the skin.

In certain embodiments, the thermal conductivity of the output opticalelement 650 has a thermal conductivity of at least approximately 10watts/meter-K. In certain other embodiments, the thermal conductivity ofthe output optical element 650 is at least approximately 15watts/meter-K. Examples of materials for the output optical element 650in accordance with certain embodiments described herein include, but arenot limited to, sapphire which has a thermal conductivity ofapproximately 23.1 watts/meter-K, and diamond which has a thermalconductivity between approximately 895 watts/meter-K and approximately2300 watts/meter-K.

In certain embodiments, the optical diffuser 640 receives and diffuseslight 626 emitted from the optical coupler 620 to advantageouslyhomogenize the light beam prior to reaching the output optical element650. Generally, tissue optics is highly scattering, so beamnon-uniformity less than approximately 3 millimeters in size has littleimpact on the illumination of the patient's cerebral cortex. In certainembodiments, the optical diffuser 640 advantageously homogenizes thelight beam to have a non-uniformity less than approximately 3millimeters. In certain embodiments, the optical diffuser 640 has adiffusing angle of approximately one degree.

In certain embodiments, the output optical element 650 receives thediffused light 626 propagating from the optical diffuser 640 and emitsthe light 626 out of the optical device 630. In certain embodiments, theoutput optical element 650 comprises a collimating lens. In certainembodiments, the light beam emitted from the output optical element 650has a nominal diameter of approximately 30 millimeters. The perimeter ofthe light beam used to determine the diameter of the beam is defined incertain embodiments to be those points at which the intensity of thelight beam is 1/e² of the maximum intensity of the light beam. Themaximum-useful diameter of certain embodiments is limited by the size ofthe patient's head and by the heating of the patient's head by theirradiation. The minimum-useful diameter of certain embodiments islimited by heating and by the total number of treatment sites that couldbe practically implemented. For example, to cover the patient's skullwith a beam having a small beam diameter would correspondingly use alarge number of treatment sites. In certain embodiments, the time ofirradiation per treatment site can be adjusted accordingly to achieve adesired exposure dose. In certain embodiments, the beam intensityprofile has a semi-Gaussian profile, while in certain other embodiments,the beam intensity profile has a “top hat” profile.

In certain embodiments, the optical device 630 comprises an optical lenswhich receives light from the optical conduit 620 and transmits thelight to the output optical element 650. In certain such embodiments,the output optical element 650 comprises an optical diffuser. In certainembodiments, the output optical element 650 comprises both an opticallens and an optical diffuser.

In certain embodiments, the optical device 630 further comprises a heatsink 660 thermally coupled to the output optical element 650 (e.g., by athermal adhesive, such as Resinlab EP1200 available from EllsworthAdhesives of Germantown, Wis.). By having the thermally conductiveoutput optical element 650 thermally coupled to the heat sink 660,certain embodiments advantageously provide a conduit for heat conductionaway from the treatment site (e.g., the skin). In certain embodiments,the output optical element 650 is pressed against the patient's skin andtransfers heat away from the treatment site. In certain otherembodiments in which the output optical element 650 is pressed againstan element 520 which contacts the patient's skin, as described above,the element 520 advantageously provides thermal conduction between thepatient's skin and the output optical element 650.

As schematically illustrated by FIG. 29, the heat sink 660 of certainembodiments comprises a reflective inner surface 662, a first end 664,and a second end 666. The heat sink 660 is positioned so that light 626from the optical diffuser 640 is transmitted into the first end 664,through the heat sink 660, out of the second end 666, and to the outputoptical element 650. The inner surface 662 of certain embodiments issubstantially cylindrical, while for certain other embodiments, theinner surface 662 is substantially conical. In certain embodimentshaving a conical inner surface 662, the inner surface 662 at the firstend 664 has a first inner diameter and the inner surface 662 at thesecond end 666 has a second inner diameter larger than the first innerdiameter.

In certain embodiments, the heat sink 660 comprises aluminum and thereflective inner surface is gold-plated. In certain other embodiments,the reflective inner surface 662 is roughened (e.g., by gritsandblasting) to reduce specular reflections of light from the innersurface 662.

In certain embodiments, as schematically illustrated by FIG. 29, theoptical device 630 further comprises a housing 670 comprising aplurality of ventilation slots 672. The ventilation slots 672 of certainembodiments allow air flow to remove heat from the heat sink 660,thereby cooling the heat sink 660.

In certain embodiments, the housing 670 is sized to be easily held inone hand (e.g., having a length of approximately 5½ inches). The housing670 of certain embodiments further comprises one or more protectivebumpers 674 comprising a shock-dampening material (e.g., rubber). Thehousing 670 of certain embodiments is configured so that the opticaldevice 630 can be held in position and sequentially moved by hand toirradiate selected portions of the patient's skin.

In certain embodiments, as schematically illustrated by FIG. 29, theoptical device 630 further comprises at least one trigger switch 680.The trigger switch 680 is electrically coupled to the source 610. Thetrigger switch 680 of certain embodiments is actuated by pressing theoutput optical element 650 against a surface. The source 610 of certainembodiments is responsive to the trigger switch 680 by emitting lightonly when the trigger switch 680 is actuated. Therefore, in certain suchembodiments, to utilize the optical device 630, the output opticalelement 650 is pressed against the patient's skin or against an element520, such as described above.

In certain embodiments, the optical device 630 further comprises athermoelectric cooler 690 thermally coupled to the output opticalelement 650, as schematically illustrated by FIG. 29. The thermoelectriccooler 690 of certain embodiments has a cool side thermally coupled tothe output optical element 650 and a hot side which is thermally coupledto the heat sink 660. The thermoelectric cooler 690 of certainembodiments advantageously removes heat from the output optical element650. Certain embodiments of the optical device 630 comprising athermoelectric cooler 690 which actively cools the patient's skinthereby advantageously avoiding large temperature gradients at thepatient's skin which would otherwise cause discomfort to the patient. Incertain embodiments, the optical device 630 further comprises one ormore temperature sensors (e.g., thermocouples, thermistors) whichgenerate electrical signals indicative of the temperature of the outputoptical element 650 or other portions of the optical device 630.

FIG. 30 schematically illustrates a simplified optical device 630compatible with certain embodiments described herein. The optical device630 of FIG. 30 has a smaller heat sink 660 and does not have athermoelectric cooler. As schematically illustrated by FIG. 30, the heatsink 660 of certain embodiments comprises a reflective conical innersurface 662 having a first end 664 with a first inner diameter and asecond end 666 with a second inner diameter larger than the first innerdiameter. In certain embodiments, the optical device 630 of FIG. 30 isadvantageously smaller, lighter, and more easily maneuvered by hand thanthe optical device 630 of FIG. 29.

FIG. 31A illustrates two beam profile cross-sections of a light beamemitted from the optical device 630 of FIG. 29 with the planes of thetwo cross-sections of FIG. 31A generally perpendicular to one anotherand to an output optical element 650 comprising a lens. The beamdiameter of FIG. 31A is approximately 30 millimeters. FIG. 31Billustrates the encircled energy of a light beam emitted from theoptical device 630 of FIG. 29. Approximately 90% of the encircled energyfalls within a diameter of approximately 25.7 millimeters.

FIG. 32A illustrates two beam profile cross-sections of a light beamemitted from the optical device 630 of FIG. 30 having a smoothgold-plated conical inner surface 662. The planes of the twocross-sections of FIG. 32A are generally perpendicular to one anotherand to the output optical element 650. The beam diameter of FIG. 32A isapproximately 30 millimeters. The light beam has a high flux region nearthe center of the beam profile. This high flux region qualifies as a hotspot, where a hot spot is defined as regions of the light beam in whichthe local flux, averaged over a 3 millimeter by 3 millimeter area, ismore than 10% larger than the average flux. FIG. 32B illustrates theencircled energy of a light beam emitted from the optical device 630 ofFIG. 30. Approximately 90% of the encircled energy falls within adiameter of approximately 25.6 millimeters.

In certain embodiments having a smooth inner surface 662, multiplereflections of light emitted from the optical fiber 622 at large enoughangles are focused near the output optical element 650, contributing tothe hot spot region of the beam profile. FIG. 33 illustrates two beamprofile cross-sections of a light beam emitted from the optical device630 of FIG. 30 having a grit sandblasted conical inner surface 662. Thisinner surface 662 is roughened to reduce the amount of specularreflections from the inner surface 662. In certain such embodiments, thebeam profile does not have a hot spot region. Certain embodiments of theoptical device 630 advantageously generate a light beam substantiallywithout hot spots, thereby avoiding large temperature gradients at thepatient's skin which would otherwise cause discomfort to the patient.

In certain embodiments, the beam divergence emitted from the outputoptical element 650 is significantly less than the scattering angle oflight inside the body tissue being irradiated, which is typicallyseveral degrees. FIGS. 34A and 34B illustrate the beam divergence forthe optical device 630 of FIG. 29 and of FIG. 30 (with the sandblastedinner surface 622), respectively. The beam divergence was measured bymeasuring the beam profile at two separate planes and comparing theincrease in beam diameter (e.g., the diameter that encircled 90% of theenergy) further from the output optical element 650. In certainembodiments, the beam divergence has a full angle of about 12 degrees.The numerical aperture of the optical device 630 of FIG. 29 isapproximately 0.152 and the numerical aperture of the optical device 630of FIG. 30 is approximately 0.134, which equates to a difference of lessthan approximately 2.5 degrees.

Methods of Light Delivery

In certain embodiments, a patient is treated by identifying a pluralityof treatment sites (e.g., at least about 10) on the patient's scalp,directing an electromagnetic radiation source to each of the treatmentsites, and propagating electromagnetic radiation from the source to eachtreatment site. In certain embodiments, the electromagnetic radiationfrom the source has a wavelength within a range between about 800nanometers and about 830 nanometers.

As described more fully below, in certain embodiments, the treatmentsites are identified using an apparatus comprising a plurality ofoptically transmissive elements, each of which corresponds to atreatment site. In certain such embodiments, each of the treatment sitesis irradiated by electromagnetic radiation from a source placed incontact with each of the optically transmissive elements. In certainother embodiments, the treatment sites are instead identified by otherindicia. For example, each of the treatment sites can be identified bymarkings made on the scalp, or by structures placed in proximity to thescalp. Each of the treatment sites can then be irradiated. In certainembodiments, each of the treatment sites is irradiated by anelectromagnetic radiation source in contact with the scalp or in contactwith an intervening optically transmissive element which contacts thescalp. In certain other embodiments, the scalp is not contacted byeither the electromagnetic radiation source or an intervening element.

In certain embodiments, each of the treatment sites is irradiated usinga single electromagnetic radiation source which is sequentially movedfrom one treatment site to another. In certain other embodiments, aplurality of sources are used to irradiate multiple treatment sitesconcurrently. In certain such embodiments, the number of sources isfewer than the number of treatments sites, and the plurality of sourcesare sequentially moved to sequentially irradiate the treatment sites.

Methods of Use of Wearable Apparatus and Light Emitting Apparatus

FIG. 35 is a flow diagram of an example method 700 for controllablyexposing at least one predetermined area of a patient's scalp to laserlight to irradiate the patient's brain. As described more fully below,the method 700 is described by referring to the wearable apparatus 500and the light emitting apparatus 600 described herein. Otherconfigurations of a wearable apparatus 500 and a light emittingapparatus 600 are also compatible with the method 700 in accordance withembodiments described herein.

The method 700 comprises providing a light emitting apparatus 600 in anoperational block 710. In certain embodiments, the light emittingapparatus 600 comprises a source 610 of laser light, an optical conduit620 optically coupled to the source 610, and an optical device 630optically coupled to the optical conduit 620. Other configurations ofthe light emitting apparatus 600 besides those in FIGS. 28-34 are alsocompatible with certain embodiments described herein.

The method 700 further comprises placing a wearable apparatus 500 overthe patient's scalp in an operational block 720. The apparatus 500comprises a body 510 and a plurality of elements 520. Each element 520has a first portion 522 which conforms to a corresponding portion of thepatient's scalp when the apparatus 500 is worn by the patient. Eachelement 520 also has a second portion 524 which conforms to the opticaldevice 630 when the optical device 630 contacts the element 520. Eachelement 520 is substantially transmissive to laser light emitted by theoptical device 630. Other configurations of the wearable apparatus 500besides those in FIGS. 19-27E are also compatible with certainembodiments described herein.

The method 700 further comprises placing the light emitting apparatus600 in contact with an element 520 corresponding to at least a portionof the predetermined area of the patient's scalp to be irradiated in anoperational block 730. The method 700 further comprises irradiating theportion of the predetermined area of the patient's scalp with lightemitted by the light emitting apparatus 600 and transmitted through theelement 520 in an operational block 740.

In certain embodiments, providing the light emitting apparatus 600 inthe operational block 710 comprises preparing the light emittingapparatus 600 for use to treat the patient. In certain embodiments,preparing the light emitting apparatus 600 comprises cleaning theportion of the light emitting apparatus 600 through which laser light isoutputted. In certain embodiments, preparing the light emittingapparatus 600 comprises verifying a power calibration of laser lightoutputted from the light emitting apparatus 600. Such verification cancomprise measuring the light intensity output from the light emittingapparatus 600 and comparing the measured intensity to an expectedintensity level.

In certain embodiments, placing the wearable apparatus 500 over thepatient's scalp in the operational block 720 comprises preparing thepatient's scalp for treatment. For example, in certain embodiments,preparing the patient's scalp for treatment comprises removing hair fromthe predetermined areas of the patient's scalp to be irradiated.Removing the hair (e.g., by shaving) advantageously reduces heating ofthe patient's scalp by hair which absorbs laser light from the lightemitting apparatus 600. In certain embodiments, placing the wearableapparatus 500 over the patient's scalp in the operational block 720comprises positioning the wearable apparatus 500 so that each element520 is in contact with a corresponding portion of the patient's scalp.

In certain embodiments, placing the light emitting apparatus 600 incontact with the element 520 in the operational block 730 comprisespressing the light emitting apparatus 600 to the element 520 so that thefirst portion 522 of the element 520 conforms to the patient's scalp andthe second portion 524 of the element 520 conforms to the light emittingapparatus 600. In certain embodiments, by pressing the light emittingapparatus 600 against the element 520 in this way, pressure is appliedto the portion of the patient's scalp in contact with the element 520 soas to advantageously blanch the portion of the patient's scalp incontact with the element 520.

In certain embodiments, irradiating the portion of the predeterminedarea of the patient's scalp in the operational block 740 comprisestriggering the outputting of light from the light emitting apparatus 600by pressing the light emitting apparatus 600 against the element 520with a predetermined level of pressure. In certain embodiments, theoutputting of light from the light emitting apparatus 600 continues onlyif a predetermined level of pressure is maintained by pressing the lightemitting apparatus 600 against the element 520. In certain embodiments,light is outputted from the light emitting apparatus 600 through theelement 520 for a predetermined period of time.

In certain embodiments, the method further comprises irradiatingadditional portions of the predetermined area of the patient's scalpduring a treatment process. For example, after irradiating a firstportion of the predetermined area corresponding to a first element 520,as described above, the light emitting apparatus 600 can be placed incontact with a second element 520 corresponding to a second portion ofthe predetermined area and irradiating the second portion of thepredetermined area with light emitted by the light emitting apparatus600 and transmitted through the element 520. The various portions of thepredetermined area of the patient's scalp can be irradiated sequentiallyto one another in a predetermined sequence. In certain embodiments, thepredetermined sequence is represented by indicia corresponding to theelements 520 of the wearable apparatus 500. In certain such embodiments,the laser emitting apparatus 600 comprises an interlock system whichinterfaces with the indicia of the wearable apparatus 500 to prevent thevarious portions of the predetermined area from being irradiated out ofthe predetermined sequence.

In certain embodiments, a system for treating a patient comprises asupport (e.g., a wearable apparatus 500 as described herein) foridentifying a plurality of sites on a patient's scalp for theapplication of therapeutic electromagnetic energy in a wavelength rangebetween about 800 nanometers and about 830 nanometers. The systemfurther comprises an instruction for use of the support in combinationwith an electromagnetic light source (e.g., a light emitting apparatus600 as described herein) of the therapeutic electromagnetic energy. Theinstruction for use in certain embodiments comprises instructionscompatible with the method 700 described herein.

In certain embodiments, a system for treating a patient comprises anelectromagnetic light source (e.g., a light emitting apparatus 600 asdescribed herein). The system further comprises an instruction for useof the electromagnetic radiation source by optically coupling the sourceto a patient's scalp at a plurality of locations to deliver atherapeutic electromagnetic energy to the patient's brain. Theinstruction for use in certain embodiments comprises instructionscompatible with the method 700 described herein.

Methods of Phototherapy

Certain embodiments utilizing phototherapy as described herein are basedat least in part on the finding described above that, for a selectedwavelength, the power density (light intensity or power per unit area,in W/cm²) or the energy density (energy per unit area, in J/cm², orpower density multiplied by the exposure time) of the light energydelivered to tissue is an important factor in determining the relativeefficacy of the phototherapy, and efficacy is not as directly related tothe total power or the total energy delivered to the tissue. In themethods described herein, power density or energy density as deliveredto a portion of the patient's brain 20, which can include an areaaffected by neurodegenerative disease (e.g., Parkinson's disease),appears to be important factors in using phototherapy to treat the brain20. Certain embodiments apply optimal power densities or energydensities to the intended target tissue, within acceptable margins oferror.

As described in U.S. Patent Application Publication Nos. 2004/0138727A1,2007/0179570A1, and 2007/0179571A1, each of which is incorporated in itsentirety by reference herein, this discovery has been is particularlyapplicable with respect to treating and saving surviving but endangeredneurons after stroke (e.g., in a zone of danger surrounding the primaryinfarct after a stroke or cerebrovascular accident). Without being boundby theory or by a specific mechanism, it is believed that light energydelivered within a certain range of power densities and energy densitiesprovides the desired biostimulative effect on the intracellularenvironment, such that proper function is returned to previouslynonfunctioning or poorly functioning mitochondria in neurons which areat risk due to stroke. The biostimulative effect may includeinteractions with chromophores within the target tissue, whichfacilitate production of ATP thereby feeding energy to injured cellswhich have experienced decreased blood flow due to the stroke. Becausestrokes correspond to blockages or other interruptions of blood flow toportions of the brain, it is thought that any effects of increasingblood flow by phototherapy are of less importance in the efficacy ofphototherapy for stroke victims. Further information regarding the roleof power density and exposure time is described by Hans H. F. I. vanBreugel and P. R. Dop Bar in “Power Density and Exposure Time of He—NeLaser Irradiation Are More Important Than Total Energy Dose inPhoto-Biomodulation of Human Fibroblasts In Vitro,” Lasers in Surgeryand Medicine, Volume 12, pp. 528-537 (1992), which is incorporated inits entirety by reference herein.

A prominent feature of early Parkinson's disease is the damage to theneuronal processes (axons and their synapses) that communicate withother neurons. Axons are thin, cylindrical processes that extend so farfrom the neuronal cell that they require an axonal transport system tosupply vital nutrients and important organelles like mitochondria andsynaptic vesicles. One recent hypothesis to explain why axons andsynapses are damaged in Parkinson's disease patients is a failure in theaxonal transport system in dopaminergic neurons.

To determine if axonal transport is defective, two different models ofsporadic Parkinson's disease have been previously used in studies by Dr.Patricia Trimmer et al. of the University of Virginia Department ofNeuroscience. In these studies, axonal transport of mitochondria wasfound to be significantly reduced in processes of Parkinson's diseasecybrids (unique human neuronal cell lines that contain the mitochondrialDNA of individual Parkinson's disease patients and which share manyimportant attributes with injured dopaminergic neurons in the brains ofParkinson's disease patients) and similar human neuronal cells exposedto rotenone (a pesticide that damages neurons in a manner that resemblesParkinson's disease). These findings strongly support the hypothesisthat reduced axonal transport plays an important role in the earlystages of Parkinson's disease.

Studies which have exposed Parkinson's disease cybrid cells androtenone-treated neuronal cells to low energy laser treatment have foundthat axonal transport of mitochondria was restored. Such studiesillustrate that low energy laser treatment can improve the supply ofvital nutrients and organelles to axons and synapses in Parkinson'sdisease to compensate at least in part for the reduced axonal transport.In view of the hypothesis that axonal transport of essential nutrientsis reduced in Parkinson's disease, certain embodiments described hereinadvantageously provide low energy laser treatment to combat thisreduction of transport. In certain embodiments described herein,delivering electromagnetic radiation to brain cells causes animprovement of mitochondrial function in irradiated neurons.

In certain embodiments, the apparatus and methods of phototherapydescribed herein increase the cerebral blood flow of the patient. Incertain such embodiments, the cerebral blood flow is increased by 10%,15%, 20%, or 25% immediately post-irradiation, as compared toimmediately prior to irradiation.

In certain embodiments, the apparatus and methods of phototherapydescribed herein are used to treat neurodegeneration. As used herein,the term “neurodegeneration” refers to the process of cell destructionresulting from primary destructive events such as stroke orcerebrovascular accident, as well as from secondary, delayed andprogressive destructive mechanisms that are invoked by cells due to theoccurrence of the primary destructive event. Primary destructive eventsinclude disease processes or physical injury or insult, includingstroke, but also include other diseases and conditions such as multiplesclerosis, amylotrophic lateral sclerosis, heat stroke, epilepsy,Alzheimer's disease, dementia resulting from other causes such as AIDS,cerebral ischemia including focal cerebral ischemia, and physical traumasuch as crush or compression injury in the CNS, including a crush orcompression injury of the brain, spinal cord, nerves or retina, or anyacute injury or insult producing neurodegeneration. Secondarydestructive mechanisms include any mechanism that leads to thegeneration and release of neurotoxic molecules, including apoptosis,depletion of cellular energy stores because of changes in mitochondrialmembrane permeability, release or failure in the reuptake of excessiveglutamate, reperfusion injury, and activity of cytokines andinflammation. Both primary and secondary mechanisms contribute toforming a “zone of danger” for neurons, wherein the neurons in the zonehave at least temporarily survived the primary destructive event, butare at risk of dying due to processes having delayed effect.

As used herein, the term “neuroprotection” refers to a therapeuticstrategy for slowing or preventing the otherwise irreversible loss ofneurons due to neurodegeneration after a primary destructive event,whether the neurodegeneration loss is due to disease mechanismsassociated with the primary destructive event or secondary destructivemechanisms.

The term “cognitive function” as used herein refers to cognition andcognitive or mental processes or functions, including those relating toknowing, thinking, learning, perception, memory (including immediate,recent, or remote memory), and judging. Symptoms of loss of cognitivefunction can also include changes in personality, mood, and behavior ofthe patient. Diseases or conditions affecting cognitive function includeAlzheimer's disease, dementia, AIDS or HIV infection, Cruetzfeldt-Jakobdisease, head trauma (including single-event trauma and long-term traumasuch as multiple concussions or other traumas which may result fromathletic injury), Lewy body disease, Pick's disease, Parkinson'sdisease, Huntington's disease, drug or alcohol abuse, brain tumors,hydrocephalus, kidney or liver disease, stroke, depression, and othermental diseases which cause disruption in cognitive function, andneurodegeneration.

The term “motor function” as used herein refers to those bodilyfunctions relating to muscular movements, primarily conscious muscularmovements, including motor coordination, performance of simple andcomplex motor acts, and the like.

The term “neurologic function” as used herein includes both cognitivefunction and motor function.

The terms “cognitive enhancement” and “motor enhancement” as used hereinrefer to the improving or heightening of cognitive function and motorfunction, respectively.

The term “neurologic enhancement” as used herein includes both cognitiveenhancement and motor enhancement.

As used herein, the term “neuroprotective-effective” as used hereinrefers to a characteristic of an amount of light energy, wherein theamount is a power density of the light energy measured in mW/cm². Aneuroprotective-effective amount of light energy achieves the goal ofpreventing, avoiding, reducing, or eliminating neurodegeneration, whichshould result in cognitive enhancement and/or motor enhancement.

The term “neurologic function enhancement effective” as used hereinrefers to a characteristic of an amount of light energy, wherein theamount is a power density of the light energy measured in mW/cm². Theamount of light energy achieves the goal of neuroprotection, motorenhancement, and/or cognitive enhancement.

Thus, a method for the treatment or enhancement of neurologic functionin a patient in need of such treatment involves delivering a neurologicfunction enhancement effective amount or a neuroprotective-effectiveamount of light energy having a wavelength in the visible tonear-infrared wavelength range to a target area of the patient's brain20. In certain embodiments, the target area of the patient's brain 20includes an area exhibiting neurodegeneration. In other embodiments, thetarget area includes portions of the brain 20 not exhibitingneurodegeneration. Without being bound by theory or by a specificmechanism, it is believed that irradiation of healthy tissue inproximity to the area exhibiting neurodegeneration increases theproduction of ATP and copper ions in the healthy tissue and which thenmigrate to cells exhibiting neurodegeneration, thereby producingbeneficial effects. Additional information regarding the biomedicalmechanisms or reactions involved in phototherapy is provided by Tiina I.Karu in “Mechanisms of Low-Power Laser Light Action on Cellular Level”,Proceedings of SPIE Vol. 4159 (2000), Effects of Low-Power Light onBiological Systems V, Ed. Rachel Lubart, pp. 1-17, which is incorporatedin its entirety by reference herein.

In certain embodiments, delivering the neuroprotective amount of lightenergy includes selecting a surface power density of the light energy atthe scalp 30 corresponding to the predetermined power density at thetarget area of the brain 20. As described above, light propagatingthrough tissue is scattered and absorbed by the tissue. Calculations ofthe power density to be applied to the scalp 30 so as to deliver apredetermined power density to the selected target area of the brain 20preferably take into account the attenuation of the light energy as itpropagates through the skin and other tissues, such as bone and braintissue. Factors known to affect the attenuation of light propagating tothe brain 20 from the scalp 30 include, but are not limited to, skinpigmentation, the presence and color of hair over the area to betreated, amount of fat tissue, the presence of bruised tissue, skullthickness, and the location of the target area of the brain 20,particularly the depth of the area relative to the surface of the scalp30. For example, to obtain a desired power density of 50 mW/cm² in thebrain 20 at a depth of 3 cm below the surface of the scalp 30,phototherapy may utilize an applied power density of 500 mW/cm². Thehigher the level of skin pigmentation, the higher the power densityapplied to the scalp 30 to deliver a predetermined power density oflight energy to a subsurface site of the brain 20.

In certain embodiments, treating a patient suffering from the effects ofneurodegenerative disease (e.g., Parkinson's disease) comprises placingthe therapy apparatus 10 in contact with the scalp 30 and adjacent thetarget area of the patient's brain 20. The target area of the patient'sbrain 20 can be previously identified such as by using standard medicalimaging techniques. In certain embodiments, treatment further includescalculating a surface power density at the scalp 30 which corresponds toa preselected power density at the target area of the patient's brain20. The calculation of certain embodiments includes factors that affectthe penetration of the light energy and thus the power density at thetarget area. These factors include, but are not limited to, thethickness of the patient's skull, type of hair and hair coloration, skincoloration and pigmentation, patient's age, patient's gender, and thedistance to the target area within the brain 20. The power density andother parameters of the applied light are then adjusted according to theresults of the calculation.

The power density selected to be applied to the target area of thepatient's brain 20 depends on a number of factors, including, but notlimited to, the wavelength of the applied light, the type of CVA(ischemic or hemorrhagic), and the patient's clinical condition,including the extent of the affected brain area. The power density oflight energy to be delivered to the target area of the patient's brain20 may also be adjusted to be combined with any other therapeutic agentor agents, especially pharmaceutical neuroprotective agents, to achievethe desired biological effect. In such embodiments, the selected powerdensity can also depend on the additional therapeutic agent or agentschosen.

In certain embodiments, the treatment per treatment site proceedscontinuously for a period of about 10 seconds to about 2 hours, morepreferably for a period of about 1 to about 10 minutes, and mostpreferably for a period of about 1 to 5 minutes. For example, thetreatment time per treatment site in certain embodiments is about twominutes. In other embodiments, the light energy is preferably deliveredfor at least one treatment period of at least about five minutes, andmore preferably for at least one treatment period of at least tenminutes. The minimum treatment time of certain embodiments is limited bythe biological response time (which is on the order of microseconds).The maximum treatment time of certain embodiments is limited by heatingand by practical treatment times. The light energy can be pulsed duringthe treatment period or the light energy can be continuously appliedduring the treatment period.

In certain embodiments, the treatment may be terminated after onetreatment period, while in other embodiments, the treatment may berepeated for at least two treatment periods. The time between subsequenttreatment periods is preferably at least about five minutes, morepreferably at least about 1 to 2 days, and most preferably at leastabout one week. In certain embodiments in which treatment is performedover the course of multiple days, the apparatus 10 is wearable overmultiple concurrent days (e.g., embodiments of FIGS. 1, 3, 9A, 10, and13). The length of treatment time and frequency of treatment periods candepend on several factors, including the functional recovery of thepatient and the results of imaging analysis of the infarct. In certainembodiments, one or more treatment parameters can be adjusted inresponse to a feedback signal from a device (e.g., magnetic resonanceimaging) monitoring the patient.

During the treatment, the light energy may be continuously provided, orit may be pulsed. If the light is pulsed, the pulses are preferably atleast about 10 nanosecond long and occur at a frequency of up to about100 kHz. In certain embodiments in which the target brain tissue to beirradiated is deeper within the brain (e.g., 4 centimeters or more belowthe dura), pulsing can be used to achieve the desired power densities atthe target brain tissue while reducing the heat load and thecorresponding temperature increases. For example, pulsing may be used toirradiate the substantia nigra of the patient's brain. In certain otherembodiments, continuous wave light may also be used.

In certain embodiments, the phototherapy is combined with other types oftreatments for an improved therapeutic effect. Treatment can comprisedirecting light through the scalp of the patient to a target area of thebrain concurrently with applying an electromagnetic field to the brain.In such embodiments, the light has an efficacious power density at thetarget area and the electromagnetic field has an efficacious fieldstrength. For example, the apparatus 50 can also include systems forelectromagnetic treatment, e.g., as described in U.S. Pat. No. 6,042,531issued to Holcomb, which is incorporated in its entirety by referenceherein. In certain embodiments, the electromagnetic field comprises amagnetic field, while in other embodiments, the electromagnetic fieldcomprises a radio-frequency (RF) field. As another example, treatmentcan comprise directing an efficacious power density of light through thescalp of the patient to a target area of the brain concurrently withapplying an efficacious amount of ultrasonic energy to the brain. Such asystem can include systems for ultrasonic treatment, e.g., as describedin U.S. Pat. No. 5,054,470 issued to Fry et al., which is incorporatedin its entirety by reference herein.

PHOTOTHERAPY EXAMPLES Example 1

An in vitro experiment was done to demonstrate one effect ofphototherapy on neurons, namely the effect on ATP production. NormalHuman Neural Progenitor (NHNP) cells were obtained cryopreserved throughClonetics of Baltimore, Md., catalog #CC-2599. The NHNP cells werethawed and cultured on polyethyleneimine (PEI) with reagents providedwith the cells, following the manufacturers' instructions. The cellswere plated into 96 well plates (black plastic with clear bottoms,Becton Dickinson of Franklin Lakes, N.J.) as spheroids and allowed todifferentiate into mature neurons over a period of two weeks.

A Photo Dosing Assembly (PDA) was used to provide precisely metereddoses of laser light to the NHNP cells in the 96 well plates. The PDAincluded a Nikon Diaphot inverted microscope (Nikon of Melville, N.Y.)with a LUDL motorized x, y, z stage (Ludl Electronic Products ofHawthorne, N.Y.). An 808 nanometer laser was routed into the rearepi-fluorescent port on the microscope using a custom designed adapterand a fiber optic cable. Diffusing lenses were mounted in the path ofthe beam to create a “speckled” pattern, which was intended to mimic invivo conditions after a laser beam passed through human skin. The beamdiverged to a 25 millimeter diameter circle when it reached the bottomof the 96 well plates. This dimension was chosen so that a cluster offour adjacent wells could be lased at the same time. Cells were platedin a pattern such that a total of 12 clusters could be lased per 96 wellplate. Stage positioning was controlled by a Silicon Graphicsworkstation and laser timing was performed by hand using a digitaltimer. The measured power density passing through the plate for the NHNPcells was 50 mW/cm².

Two independent assays were used to measure the effects of 808 nanometerlaser light on the NHNP cells. The first was the CellTiter-GloLuminescent Cell Viability Assay (Promega of Madison, Wis.). This assaygenerates a “glow-type” luminescent signal produced by a luciferasereaction with cellular ATP. The CellTiter-Glo reagent is added in anamount equal to the volume of media in the well and results in celllysis followed by a sustained luminescent reaction that was measuredusing a Reporter luminometer (Turner Biosystems of Sunnyvale, Calif.).Amounts of ATP present in the NHNP cells were quantified in RelativeLuminescent Units (RLUs) by the luminometer.

The second assay used was the alamarBlue assay (Biosource of Camarillo,Calif.). The internal environment of a proliferating cell is morereduced than that of a non-proliferating cell. Specifically, the ratiosof NADPH/NADP, FADH/FAD, FMNH/FMN and NADH/NAD, increase duringproliferation. Laser irradiation is also thought to have an effect onthese ratios. Compounds such as alamarBlue are reduced by thesemetabolic intermediates and can be used to monitor cellular states. Theoxidization of alamarBlue is accompanied by a measurable shift in color.In its unoxidized state, alamarBlue appears blue; when oxidized, thecolor changes to red. To quantify this shift, a 340PC microplate readingspectrophotometer (Molecular Devices of Sunnyvale, Calif.) was used tomeasure the absorbance of a well containing NHNP cells, media andalamarBlue diluted 10% v/v. The absorbance of each well was measured at570 nanometers and 600 nanometers and the percent reduction ofalamarBlue was calculated using an equation provided by themanufacturer.

The two metrics described above, (RLUs and % Reduction) were then usedto compare NHNP culture wells that had been lased with 50 mW/cm² at awavelength of 808 nanometers. For the CellTiter-Glo assay, 20 wells werelased for 1 second and compared to an unlased control group of 20 wells.The CellTiter-Glo reagent was added 10 minutes after lasing completedand the plate was read after the cells had lysed and the luciferasereaction had stabilized. The average RLUs measured for the control wellswas 3808+/−3394 while the laser group showed a two-fold increase in ATPcontent to 7513+/−6109. The standard deviations were somewhat high dueto the relatively small number of NHNP cells in the wells (approximately100 per well from visual observation), but a student's unpaired t-testwas performed on the data with a resulting p-value of 0.02 indicatingthat the two-fold change is statistically significant.

The alamarBlue assay was performed with a higher cell density and alasing time of 5 seconds. The plating density (calculated to be between7,500-26,000 cells per well based on the certificate of analysisprovided by the manufacturer) was difficult to determine since some ofthe cells had remained in the spheroids and had not completelydifferentiated. Wells from the same plate can still be compared though,since plating conditions were identical. The alamarBlue was addedimmediately after lasing and the absorbance was measured 9.5 hourslater. The average measured values for percent reduction were 22%+/−7.3%for the 8 lased wells and 12.4%+/−5.9% for the 3 unlased control wells(p-value=0.076). These alamarBlue results support the earlier findingsin that they show a similar positive effect of the laser treatment onthe cells.

Increases in cellular ATP concentration and a more reduced state withinthe cell are both related to cellular metabolism and are considered tobe indications that the cell is viable and healthy. These results arenovel and significant in that they show the positive effects of laserirradiation on cellular metabolism in in-vitro neuronal cell cultures.

Example 2

In a second example, transcranial laser therapy for stroke wasinvestigated using a low-energy infrared laser to treat behavioraldeficits in a rabbit small clot embolic stroke model (RSCEM). Thisexample is described in more detail by P. A. Lapchak et al.,“Transcranial Infrared Laser Therapy Improves Clinical Rating ScoresAfter Embolic Strokes in Rabbits,” Stroke, Vol. 35, pp. 1985-1988(2004), which is incorporated in its entirety by reference herein.

RSCEM was produced by injection of blood clots into the cerebralvasculature of anesthetized male New Zealand White rabbits, resulting inischemia-induced behavioral deficits that can be measured quantitativelywith a dichotomous rating scale. In the absence of treatment, smallnumbers of microclots caused no grossly apparent neurologic dysfunctionwhile large numbers of microclots invariably caused encephalopathy ordeath. Behaviorally normal rabbits did not have any signs of impairment,whereas behaviorally abnormal rabbits had loss of balance, head leans,circling, seizure-type activity, or limb paralysis.

For laser treatment, a laser probe was placed in direct contact with theskin. The laser probe comprised a low-energy laser (wavelength of 808±5nanometers) fitted with an OZ Optics Ltd. fiber-optic cable and a laserprobe with a diameter of approximately 2 centimeters. Instrument designstudies showed that these specifications would allow for laserpenetration of the rabbit skull and brain to a depth of 2.5 to 3centimeters, and that the laser beam would encompass the majority of thebrain if placed on the skin surface posterior to bregma on the midline.Although the surface skin temperature below the probe was elevated by upto 3° C., the focal brain temperature directly under the laser probe wasincreased by 0.8° C. to 1.8° C. during the 10-minute laser treatmentusing the 25 mW/cm² energy setting. Focal brain temperature returned tonormal within 60 minutes of laser treatment.

The quantitative relationship between clot dose and behavioral orneurological deficits was evaluated using logistic (S-shaped) curvesfitted by computer to the quantal dose-response data. These parametersare measures of the amount of microclots (in mg) that producedneurologic dysfunction in 50% of a group of animals (P₅₀). A separatecurve was generated for each treatment condition, with a statisticallysignificant increase in the P₅₀ value compared with control beingindicative of a behavioral improvement. The data were analyzed using thet test, which included the Bonferroni correction when appropriate.

To determine if laser treatment altered physiological variables, 14rabbits were randomly divided into 2 groups, a control group and alaser-treated group (25 mW/cm² for 10 minutes). Blood glucose levelswere measured for all embolized rabbits using a Bayer Elite XL 3901 BGlucometer, and body temperature was measured using a Braun ThermoscanType 6013 digital thermometer. Within 60 minutes of embolization, therewas an increase in blood glucose levels in both the control group andthe laser-treated group that was maintained for the 2 hourspost-embolization observation time. Blood glucose levels returned tocontrol levels by 24 hours, regardless of the extent of stroke-inducedbehavioral deficits. Laser treatment did not significantly affectglucose levels at any time. Neither embolization nor laser treatmentsignificantly affected body temperature in either group of rabbits.

FIG. 17A is a graph for the percentage of the population which waseither abnormal or dead as a function of the clot weight in milligramsfor laser treatment of 7.5 mW/cm² for a treatment duration of 2 minutes.As shown by FIG. 17A, the control curve (dotted line) has a P₅₀ value of0.97±0.19 mg (n=23). Such laser treatment initiated 3 hours after thestroke significantly improved behavioral performance, with the P₅₀ valueincreased to 2.21±0.54 mg (n=28, *P=0/05) (solid line). The effect wasdurable and was measurable 3 weeks after embolization. However, the samesetting did not improve behavior if there was a long delay (24 hours)after embolization (dashed line) (P₅₀=1.23±0.15 mg, n=32).

FIG. 17B is a graph for the percentage of the population which waseither abnormal or dead as a function of the clot weight in milligramsfor laser treatment of 25 mW/cm2 for a treatment duration of 10 minutes.As shown by FIG. 17B, the control curve (dotted line) has a P₅₀ value of1.10±0.17 mg (n=27). Such laser treatment initiated 1 (dashed line) or 6(solid line) hours after embolization also significantly increasedbehavioral performance, with the P₅₀ value increased to 2.02±0.46 mg(n=18, *P<0.05) and 2.98±0.65 mg (n=26, *P<0.05), respectively.

FIG. 18 is a graph showing the therapeutic window for laser-inducedbehavioral improvements after small-clot embolic strokes in rabbits.Results are shown as clinical rating score P₅₀ (mg clot) given as mean±SEM for the number of rabbits per time point (number in brackets) forlaser treatment initiated 1, 3, 6, or 24 hours after embolization asshown on the x-axis. The horizontal line represents the mean of thecontrol P₅₀ values (*P<0.05).

The results in the RSCEM showed that laser treatment significantlyimproved behavioral rating scores after embolic strokes in rabbitswithout affecting body temperature and blood glucose levels. Inaddition, laser treatment was effective when initiated up to 6 hoursafter strokes, which is later than any other previously effective singletherapy in the same preclinical stroke model. Moreover, the effect wasdurable and was measurable up to 21 days after embolization. Themagnitudes of laser-induced improvement in rabbits are similar topreviously tested thrombolytics (alteplase, tenecteplase, andmicroplasmin) and neuroprotective compounds (NXY-059), which areundergoing clinical development.

Neurologic Function Scales

Neurologic function scales can be used to quantify or otherwisecharacterize the efficacy of various embodiments described herein.Neurologic function scales generally use a number of levels or points,each point corresponding to an aspect of the patient's condition. Thenumber of points for a patient can be used to quantify the patient'scondition, and improvements in the patient's condition can be expressedby changes of the number of points. One example neurologic functionscale used as a clinical tool for diagnosis and determining severity ofParkinson's disease is the Unified Parkinson's Disease Rating Scale(UPDRS) which comprises various sections evaluated by interview andclinical observation. In certain embodiments, two or more of theneurologic function scales can be used in combination with one another,and can provide longer-term measurements of efficacy (e.g., at threemonths).

In certain embodiments described herein, a patient exhibiting symptomsof Parkinson's disease is treated by irradiating a plurality oftreatment sites on the patient's scalp. The irradiation is performedutilizing irradiation parameters (e.g., wavelength, power density, timeperiod of irradiation, etc.) which, when applied to members of a treatedgroup of patients, produce at least a 2% average difference between thetreated group and a placebo group on at least one neurologic functionscale (e.g., UPDRS) analyzed in dichotomized or any other fashion.Certain other embodiments produce at least a 4% average difference, atleast a 6% average difference, or at least a 10% average differencebetween treated and placebo groups on at least one neurologic functionscale analyzed in dichotomized or any other fashion. In certainembodiments, the irradiation of the patient's scalp produces a change inthe patient's condition. In certain such embodiments, the change in thepatient's condition corresponds to a change in the number of pointsindicative of the patient's condition. In certain such embodiments, theirradiation produces a change of one point, a change of two points, achange of three points, or a change of more than three points on aneurologic function scale.

Possible Action Mechanisms

The following section discusses theories and potential actionmechanisms, as they presently appear to the inventors, for certainembodiments of phototherapy described herein. The scope of the claims ofthe present application is not to be construed to depend on theaccuracy, relevance, or specifics of any of these theories or potentialaction mechanisms. Thus the claims of the present application are to beconstrued without being bound by theory or by a specific mechanism.

It is well known that light can produce profound biological effects suchas vision, regulation of circadian hormones, melanin production, andVitamin D synthesis. It has also been shown that specific wavelengths oflight targeted at the cytochrome C receptor in the mitochondria candramatically preserve function, as well as, reduce the size ofmyocardial infarcts and stroke. It has also been shown that theseeffects can be reproduced across multiple species. This is notsurprising since the mitochondrial target receptor (i.e., copper ions incytochrome C) is conserved between species. These effects may be due toproduction of new cells (neurogenesis), preservation of existing tissue(neuroprotection) or a combination of both.

The clinical and cellular responses to light for in vivo treatmentefficacy of ischemic conditions of acute myocardial infarction andstroke has been demonstrated in multiple validated animal models. Asdescribed more fully below, these effects are wavelength-specific.Without being bound by theory or by a specific mechanism, the wavelengthspecificity may be dependent upon a known mitochondrial receptor(cyctochrome C oxidase). Targeting of this receptor may result information of adenosine triphosphate (ATP), enhanced mitochondrialsurvival, and maintenance of cytochrome C oxidase activity.

In stroke, the occlusion of a major artery results in a core area ofsevere ischemia (e.g., with blood flow reduced to less than 20% ofpre-occlusion levels). The core area has a rapid loss of ATP and energyproduction, and the neurons are depolarized. This core of the infarct issurrounded by an ischemic penumbra which can be up to twice as large asthe core of the infarct. Cells within the penumbra show less severedecreases in loss of blood flow (e.g., 20 to 40% of normal). Neurons inthe penumbra tend to be hyperpolarized and electrically silent. In thepenumbra, the cells undergo progression of cell death lasting from hoursto days after the infarct. Also, inflammation after infarct can play arole in determining the final infarct size and anti-inflammatorymodulators can reduce infarct size. The infarct is dynamic, withdifferent parts of the infarct being affected to different degrees overa period of hours to days. Photon therapy has been implicated in anumber of physiological processes that could favor cell survival in thepenumbral region of a stroke.

In Vitro

The action of light on a cell is mediated by one or more specific photoacceptors. A photo acceptor molecule first absorbs the light. After thisabsorptive event and promotion of an electron to an excited state, oneor more primary molecular processes from these high energy states canlead to a measurable biological effect at the cellular level. An actionspectra represents the biological activity as a function of wavelength,frequency or photon energy. Karu was the first researcher to proposethat the action spectra should resemble the absorption spectra of thephotoacceptor molecule. Since an absorptive event occurs for a transferof energy to take place, the stimulatory wavelengths of the actionspectra falls within the absorptive spectra of the photo acceptor.

Karu was also the first to propose a specific mechanism for photontherapy at the cellular level (see, e.g., T. Karu, “PhotobiologicalFundamentals of Low Power Laser Therapy,” IEEE Journal of QuantumElectronics, 1987, Vol. 23, page 1703; T. Karu, “Mechanisms ofinteraction of monochromatic visible light with cells,” Proc. SPIE,1995, Vol. 2630, pages 2-9). Karu's hypothesis was based on theabsorption of monochromatic visible and near infrared radiation bycomponents of the cellular respiratory chain. Absorption and promotionof electronically excited states cause changes in redox properties ofthese molecules and acceleration of electron transfer (primaryreactions). Primary reactions in mitochondria of eukaryotic cells arefollowed by a cascade of secondary reactions occurring in the cytoplasm,cell membrane, and nucleus. Karu defined the action spectra formammalian cells of several secondary reactions (DNA, RNA synthesis,cellular adhesion). The action spectra for all of these secondarymarkers were very similar, suggesting a common photo acceptor. Karu thencompared these action spectra with absorption spectra of the coppercenters of cytochrome C oxidase in both reduced and oxidized states.Cytochrome C oxidase contains four redox active metal centers and has astrong absorbance in the near infrared spectral range. The spectralabsorbance of cytochrome C oxidase and the action spectra were verysimilar. Based on this, Karu suggested that the primary photoacceptorsare mixed valence copper centers within cytochrome C oxidase.

Cytochrome C oxidase is the terminal enzyme of the mitochondrialelectron transport chain of all eukaryotes and is required for theproper function of almost all cells, especially those of highlymetabolically active organs, such as the brain and heart. Cytochrome Chas also been suggested to be the critical chromophore responsible forstimulatory effects of irradiation with infrared light to reverse thereduction in cytochrome C oxidase activity produced by the blockade ofvoltage dependent sodium channels with tetrodotoxin and up regulatedcytochrome C activity in primary neuronal cells. It has beendemonstrated by researchers (see, e.g., M. T. Wong-Riley et al.,NeuroReport, 2001, Vol. 12, pages 3033-3037; J. T. Eells et al.,Proceedings National Academy of Science, 2003, Vol. 100, pages3439-3444) that in vivo, rat retinal neurons are protected from damageinduced by methanol intoxication. Methanol's toxic metabolite is formicacid which inhibits cytochrome C.

Several investigators have demonstrated the increased synthesis of ATPfrom infrared irradiation both in vitro and in vivo. Karu has shown thatirradiation of cells in vitro at wavelengths of 632 nanometers, 670nanometers, and 820 nanometers can increase mitochondrial activity.

In Vivo

There are numerous studies, both published and unpublished,demonstrating the effectiveness of photon therapy in animal models foracute myocardial infarction (AMI) and ischemic stroke. These studiessuggest that photon therapy induces a cascade of signaling eventsinitiated by the initial absorption of light by cytochrome C. Thesesignaling events apparently up-and-down regulate genes, transcriptionfactors, as well as increase mitochondrial function.

Without being bound by theory or a specific mechanism, in stroke,reduction of infarct volume may occur in one of two ways or acombination of both: (i) preservation of existing tissue(neuroprotection), and (ii) generation of new tissue (neurogenesis). Anumber in vitro and in vivo studies appear to support both of thesepotential mechanisms. The potential effects of NIR light on neurogenesisare straightforward; it either increases the number of new cells, or itprevents the loss of new cells that are generated as a result of theischemic insult. Neuroprotection can result from at least threemechanisms: (i) direct stimulation of tissue survival; (ii) indirectstimulation of tissue survival (e.g., increased growth factor activity);and (iii) decrease in toxic factors.

FIG. 36 is a graph which shows mediators responsible for ischemic stroketissue damage and the time points at which they occur. FIG. 36illustrates several potential places where photon therapy couldpotentially intervene to reduce infarct severity. Early after ischemicstroke, excitatory amino acids (EAAs) induce Ca²⁺ influx via NMDAreceptor activation leading to neuronal and glial cell injury. A numberof immediately early genes (IEGs) express such as c-fos, c-jun, within30 minutes. Reactive oxygen species (ROSs) create lipid peroxidation andactivated phagocytes which create further injury. ROSs damage mostcellular components. Cytokines are then expressed causing migration ofpolymorphonuclear neutrophils (PMNs) into the ischemic brain.Macrophages and neutrophils follow into the brain parenchyma. Apoptosisoccurs via caspase activation which further increases stroke damage.

Preservation of existing tissue (neuroprotection) can result from directstimulation of the tissue (e.g., by ATP synthesis or by prevention ofcytochrome C release from mitochondria). Ischemia results in depletionof ATP in the ischemic zone due to lack of oxygen and glucose. Theresultant lack of ATP, depending on severity, results in decreasedcellular function. In extreme cases, energy depletion leads to celldepolarization, calcium influx, and activation of necrotic and apoptoticprocesses. Near-infrared radiation (NIR) stimulates the production ofATP in a variety of cell types in culture, and in cardiac tissue. Asingle irradiation of infarcted cardiac tissue results in astatistically significant 3-fold increase in tissue ATP levels fourhours after treatment. The effect of NIR is prolonged long afterirradiation is ceased. The prolonged effect could also be due, in part,to preservation of mitochondrial function. NIR irradiated, infarctedcardiac tissue has exhibited over a 50% reduction in damagedmitochondria. After ischemia, the myocardial tissue that is notimmediately lost is in a “stunned” state, and can remain stunned for aperiod of days. In particular, it is the mitochondria in the tissue thatare stunned. Stunned mitochondria are still intact, but withcharacteristic morphological changes that are indicative of mitochondriathat are not metabolically active. As such, even with restored bloodflow, the mitochondria are unable to convert oxygen and glucose touseable energy (ATP).

Neuroprotection can also result from direct stimulation of the tissue bypreventing cytochrome C release from mitochondria. The release ofcytochrome C from the mitochondria into the cytoplasm is a potentapoptotic signal. Cytochrome C release results in the activation ofcaspase-3 and activation of apoptotic pathways. The apoptotic cellsappear as soon as a few hours after stroke, but the cell numbers peak at24 to 48 hours after reperfusion. In rat models of stroke, cytoplasmiccytochrome C can be detected out to at least 24 hours after theocclusion. In vitro 810-nanometer light can prevent the TTX-induceddecrease in cytochrome oxidase activity. Photon therapy may also be ableto maintain cytochrome oxidase activity in vivo by preventing release ofcytochrome C into the cytoplasm, resulting in the prevention ofapoptosis. The release of cytochrome C is regulated by the Bcl/Baxsystem. Bax promotes release and Bcl decreases release. In myofibercultures in vitro, NIR light promotes Bcl-2 expression and inhibits Baxexpression, which fits with the prevention of cytochrome C release data.

Neuroprotection can also result from indirect stimulation (e.g., byangiogenesis or by up-regulation of cell survival genes and/or growthfactors). Regarding angiogenesis and stroke, recent research indicatesthat the reduction in cerebral blood flow (CBF) can lead to compensatoryneovascularization in the affected regions. The low CBF results in theup regulation of hypoxia inducible factor-1 (HIF-1), vascularendothelial growth factor (VEGF), and VEGF receptors. In the rat pMCAomodel, infusion of VEGF results in a reduction of infarct size. In AMImodels, VEGF is increased with photon therapy.

Regarding up-regulation of cell survival genes and/or growth factors, ithas been shown that photon therapy may up-, and down-regulate certainbeneficial genes. It is possible that these gene products can prevent orameliorate apoptosis, which is known to occur throughout the stokepenumbra and in stunned myocardium of AMI. In AMI models, expression ofthe cardioprotective molecules HSP70 and VEGF are increased. In stroke,equivalent neuroprotective molecules could be up-regulated, preservingtissue and resulting in reduction of infarct volumes. A variety offactors have been implicated in neuroprotection in addition to VEGF,including BDNF, GDNF, EGF, FGF, NT-3, etc. There are a number of factorsthat could be up-regulated to promote neuronal survival, at least one ofwhich is increased due to NIR light treatment.

Neuroprotection can also result from decreases in toxic factors (e.g.,antioxidant protection or by reduction of deleterious factors to tissuefunction and survival). Regarding antioxidant protection, NIR light mayreduce damage induced by free radicals. By-products of free radicaldamage are found in damaged brain tissue following stroke. This damageis thought to be mediated by neutrophils during reperfusion injury. Thenominal spin-trap agent NXY-059 (a free radical scavenger) reducesinfarct size if given within 2.25 hours of a stroke (in rat, although itis more effective if given sooner). NIR light can induce the expressionof catalase in AMI models. Catalase is a powerful anti-oxidant which canprevent free radical damage and, if produced in the area of the stroke,it may prevent loss via the same mechanism as NXY-059. Axon survival isknown to be improved by catalase.

In addition, a number of cytokines and other factors are produced duringreperfusion that are deleterious to tissue function and survival. Thesefactors promote activity of existing phagocytic and lymphocytic cells aswell as attract additional cells to the area of damage. NIR light candecrease the levels of cytokines in models of neuronal damage. Inparticular, IL-6 and MCP-1 (pro-inflammatory cytokines) are induced inmodels of spinal cord damage. NIR light significantly reduces IL-6 andMCP-1 and promotes regrowth of the spinal cords neurons. IL-6 is thoughtto play a significant role in spinal cord damage in man also.

Regarding neurogenesis, in the last several years, it has been becomewell-established that the brain has the ability to generate new nervecells in certain instances. Neural stem cells have been shown to existin the periventricular areas and in the hippocampus. Naturally-occurringgrowth factors in the adult human brain can spur the production of newnerve cells from these stem cells. After a stroke, neurogenesiscommences in the hippocampus with some cells actually migrating to thedamaged area and becoming adult neurons.

NIR light may be effective by either increasing the number of new cellsthat are formed, or by preventing the loss of the newly formed cells.The latter may be more significant and the majority of newly-formedcells die within 2 to 5 weeks after the stroke (rat model). In anunpublished study by Oron, NIR light has been shown to increase thesurvival of cardiomyocytes implanted into infarcted heart. Other studieshave shown the human neural progenitor cells can be induced todifferentiate with stimulation of 810-nanometer irradiation without thepresence of specific growth factors that are normally required fordifferentiation. These data suggest that neurogenesis could occur if theinfrared irradiation were to act as a stimulating signal much like agrowth factor. Early data from a porcine study of AMI has shown that the810-nanometer-irradiated pig myocardium showed evidence ofcardiogenesis. This result was demonstrated by the presence ofsignificant desmin staining in the laser treated group over control, andby ultrastructural analysis which demonstrated the presence of whatappears to be developing cardiomyocytes.

Wavelength Selection

The following section discusses theories and potential actionmechanisms, as they presently appear to the inventors, regarding theselection of wavelengths for certain embodiments of phototherapydescribed herein. The scope of the claims of the present application isnot to be construed to depend on the accuracy, relevance, or specificsof any of these theories or potential action mechanisms. Thus the claimsof the present application are to be construed without being bound bytheory or by a specific mechanism.

In certain embodiments, non-invasive delivery and heating by theelectromagnetic radiation place practical limits on the ranges ofelectromagnetic radiation wavelengths to be used in the treatment of thepatient's brain. In certain embodiments, the wavelength ofelectromagnetic radiation used in the treatment of the patient's brainis selected in view of one or more of the following considerations: (1)the ability to stimulate mitochondrial function in vitro; (2) theability to penetrate tissue; (3) the absorption in the target tissue;(4) the efficacy in ischemia models in vivo; and (5) the availability oflaser sources with the desired power at the desired wavelength orwavelengths. The combination of these effects offers few wavelengths tobe used as a therapeutic agent in vivo. These factors can be combined incertain embodiments to create an efficiency factor for each wavelength.Wavelengths around 800 nanometers are particularly efficient. Inaddition, 808-nanometer light has previously been found to stimulatemitochondrial function and to work in the myocardial infarction modelsin rat and dog. The following discussion deals with these considerationsin more detail.

Photostimulation Effects on Mitochondria

The mitochondria convert oxygen and a carbon source to water and carbondioxide, producing energy (as ATP) and reducing equivalents (redoxstate) in the process. The process details of the electron transportchain in mitochondria are schematically diagrammed in FIG. 37. Thechemical energy released from glucose and oxygen is converted to aproton gradient across the inner membrane of the mitochondria. Thisgradient is, in turn, used by the ATPase complex to make ATP. Inaddition, the flow of electrons down the electron transfer chainproduces NADPH and NADH (and other factors such as FAD). These cofactorsare important for maintaining the redox potential inside the cell withinthe optimal range. This process has been called the chemi-osmotic theoryof mitochondrial function (Dr. Peter Mitchell was awarded a Nobel Prizein chemistry for elucidating these key processes).

There are five large components of the electron transfer chain,Complexes I-IV and the ATPase (also called Complex V), with each complexcontaining a number of individual proteins (see FIG. 37). One of thecritical complexes, Complex IV (cytochrome oxidase), is the componentresponsible for the metabolism of oxygen. The cytochrome C oxidaseprotein is a key player in the electron transfer in Complex IV throughits copper centers. These copper centers have been proposed as importantchromophores (photoacceptors) for the absorption of light energy in thenear infra-red region.

As an aside, cytochrome C oxidase has enjoyed a renaissance in the lastfew years as an important factor in the regulation of apoptosis(programmed cell death). Release of cytochrome C oxidase from themitochondria into the cytosol is a pro-apoptotic signal.

It has been postulated by others that light can directly activateComplex IV and indirectly driving the production of ATP via ATPase (andreducing equivalents). For example, Karu studied the activation spectraof these processes and found that wavelengths that maximally stimulatedenergy-dependant cellular functions corresponded to the absorption bandsof the copper centers in cytochrome C oxidase. FIG. 38 is a graph ofcell proliferation and cytochrome oxidase activity percentage asfunctions of the wavelength of light used to stimulate mammalian cells.Based on these results, wavelengths of 620, 680, 760, and 820 nanometers(110 nanometers) promote cellular activities. The 620 and 820 nanometerwavelengths are close to the strongest copper absorption maxima of 635and 810 nanometers.

Additional data from other groups suggest that cytochrome C oxidase isan important target. Light (670 nanometers) can rescue primary neuronsfrom the toxic effects of the sodium channel blocker tetrodotoxin (TTX).TTX reduces cytochrome oxidase activity in treated neurons, and thisreduction is reversed by light treatment (an increase in cytochromeoxidase activity). In an in vivo model, 670 nanometer light is used torescue retinal function in a methanol-mediated model of retinal damage.Methanol is metabolized to formate, a selective mitochondrial toxintargeted at cytochrome C oxidase. Irradiation with light (670nanometers) rescued the retina from damage induced by methanol.

Tissue Penetration and Absorption

In vitro and near in vitro like conditions (retinal studies) havepreviously demonstrated that light can induce beneficial effects inanimals. Yet these effects required little if any ability to penetratenon-involved tissues. For treatments of Parkinson's disease byirradiation through intervening tissue, certain embodiments utilizewavelengths that can penetrate to the target tissue.

Light can be absorbed by a variety of chromophores. Some chromophores,such as cytochrome C oxidase can convert the light energy into chemicalenergy for the cell. Other chromophores can be simple and the lightenergy is converted to heat, for example water. The absorption of lightenergy is wavelength dependent and chromophore dependant.

Some chromophores, such as water or hemoglobin, are ubiquitous andabsorb light to such a degree that little or no penetration of lightenergy into a tissue occurs. For example, water absorbs light aboveapproximately 1300 nanometers. Thus energy in this range has littleability to penetrate tissue due to the water content. However, water istransparent or nearly transparent in wavelengths between 300 and 1300nanometers. Another example is hemoglobin, which absorbs heavily in theregion between 300 and 670 nanometers, but is reasonably transparentabove 670 nanometers.

Based on these broad assumptions, one can define an “IR window” into thebody. Within the window, there are certain wavelengths that are more orless likely to penetrate. This discussion does not include wavelengthdependent scattering effects of intervening tissues.

The absorption/transmittance of various tissues have been directlymeasured to determine the utility of various wavelengths. FIG. 39 is agraph of the transmittance of light through blood (in arbitrary units)as a function of wavelength. Blood absorbs less in the region above 700nanometers, and is particularly transparent at wavelengths above 780nanometers. Wavelengths below 700 nanometers are heavily absorbed, andare not likely to be useful therapeutically (except for topicalindications).

FIG. 40 is a graph of the absorption of light by brain tissue.Absorption in the brain is strong for wavelengths between 620 and 900nanometers. This range is also where the copper centers in mitochondriaabsorb. The brain is particularly rich in mitochondria as it is a veryactive tissue metabolically (the brain accounts for 20% of blood flowand oxygen consumption). As such, the absorption of light in the 620 to900 nanometer range is expected if a photostimulative effect is to takeplace.

By combining FIGS. 39 and 40, the efficiency of energy delivery as afunction of wavelength can be calculated, as shown in FIG. 41.Wavelengths between 780 and 880 nanometers are preferable (efficiency of0.6 or greater) for targeting the brain. The peak efficiency is about800 to 830 nanometers (efficiency of 1.0 or greater). These wavelengthsare not absorbed by water or hemoglobin, and are likely to penetrate tothe brain. Once these wavelengths reach the brain, they will be absorbedby the brain and converted to useful energy.

These effects have been directly demonstrated in rat tissues. Theabsorption of 808 nanometer light was measured through various rattissues, as shown in FIG. 42. Soft tissues such as skin and fat absorblittle light. Muscle, richer in mitochondria, absorbs more light. Evenbone is fairly transparent. However, as noted above, brain tissue, aswell as spinal cord tissue, absorb 808 nanometer light well.

Efficacy in Other Tissues

Two wavelengths have demonstrated efficacy in animal models ofischemia/mitochondrial damage, namely, 670 nanometers and 808nanometers. Light having a wavelength of 670 nanometers has shownefficacy in retinal damage. Light having a wavelength of 808 nanometershas demonstrated efficacy in animal models of myocardial infarction (aswell as soft tissue injury).

The effects of near infrared light on soft tissue injury have beenestablished in FDA approved trials for carpal tunnel syndrome (830nanometers) and knee tendonitis (830 nanometers). In both cases, 830nanometer light was superior to placebo for resolution of symptoms.

Light having a wavelength of 808 nanometers was also used to reduceinfarct volume and mortality in myocardial infarction (MI) models inrat, dog, and pig. The MI models are particularly relevant to wavelengthselection as similar processes—apoptosis, calcium flux, mitochondrialdamage—have been implicated in stroke and MI.

Certain wavelengths of light are associated with activation ofbiological processes, and others are not. In particular, light mediatedmitochondrial activation has been used as a marker of biostimulation.Given the lack of in vivo markers, the use of in vitro markers of lightactivation was used to help narrow down the large number of potentialwavelengths. Wavelengths that activate mitochondria were determined, andthese wavelengths were used in vivo models.

Penetration to the target tissue is also of importance. If a biologicaleffect is to be stimulated, then the stimulus must reach the targettissue and cell. In this regard, wavelengths between 800 and 900nanometers are useful, as they can penetrate into the body. Inparticular, wavelengths of 800 to 830 nanometers are efficient atpenetrating to the brain and then being absorbed by the brain.

The use of 808 nanometer light has a solid basis for the treatment ofstroke. This wavelength of light can penetrate to the target tissue(brain), is absorbed by the target tissue, stimulates mitochondrialfunction, and works in a related animal model of ischemia (MI). Thissupposition is supported by the striking finding that 808 nanometerlight can reduce the neurological deficits and infarct volume associatedwith stroke (in rats).

Other wavelengths have some of these properties. For example, 670nanometer light can promote mitochondrial function and preserve retinalneurons. However, this wavelength does not penetrate tissue well as itis highly absorbed by hemoglobin. It is therefore not useful in treatingstroke or neurodegenerative conditions.

In certain embodiments, wavelengths from 630 to 904 nanometers may beused. This range includes the wavelengths that activate mitochondria invitro, and that have effects in animal models. These wavelengths alsoinclude the predominant bands that can penetrate into the body.

Transmission in Human Brain

Power density measurements have been made to determine the transmissionof laser light having a wavelength of approximately 808 nanometersthrough successive layers of human brain tissue. Laser light having awavelength of (808±5) nanometers with a maximum output of approximately35 Watts was applied to the surface of the cortex using a beam deliverysystem which approximated the beam profile after the laser light passesthrough the human skull. Peak power density measurements were takenthrough sections of human brain tissue using an Ocean Opticsspectrophotometer Model USB 2000, Serial No. G1965 and beam diameterafter scattering was approximated using a Sony Model DCR-IP220, SerialNo. 132289.

A fresh human brain and spinal cord specimen (obtained within six hoursafter death) was collected and placed in physiologic Dakins solution.The pia layer, arachnoid layer, and vasculature were intact. The brainwas sectioned in the midline sagittaly and the section was placed in acontainer and measurements taken at thicknesses of 4.0 centimeters (±0.5centimeter), 2.5 centimeters (±0.3 centimeter), and 1.5 centimeters(±0.2 centimeter). The power density measurements are shown in Table 2:

TABLE 2 Thickness Power density at cortex Average power density atthickness 4.0 cm 20 mW/cm² 4.9 μW/cm²  2.5 cm 20 mW/cm² 20 μW/cm² 1.5 cm10 mW/cm² 148 μW/cm² FIG. 43 is a graph of the power density versus the depth from the durafor an input power density of 10 mW/cm² with the light barscorresponding to predicted values of the power density and dark barscorresponding to an estimated minimum working power density of 7.5μW/cm², as described below.

Based upon prior animal experimentation, a conservative estimation ofthe minimum known power density within the tissue of the brain which isable to show efficacy in stroke animal models is 7.5 μW/cm². Thisestimated minimum working power density is drawn from an experiment inwhich 10 mW was applied to the rat brain surface, and 7.5 μW/cm² powerdensity was directly measured 1.8 centimeters from the surface. Thisstroke model consistently produced significant efficacy, including forstrokes 1.8 centimeters from the laser probe. Note that this 7.5 μW/cm²is a conservative estimate; the same power density at the brain surfacealso consistently produces significant efficacy in the 3 centimeterrabbit clot shower model. Note also that the power density measurementsin the human brain experiment do not factor in the effect from theCNS-filled sulci, through which the laser energy should be readilytransmitted. However, even conservatively assuming 7.5 μW/cm² as theminimum power density hurdle and ignoring expected transmission benefitsfrom the sulci, the experiment described above confirms thatapproximately 10-15 mW/cm² transmitted upon the cortex (as per anexample dosimetry in man) will be effective to at least 3.0 centimetersfrom the surface of the brain.

In Vivo Thermal Measurements

In vivo thermal measurements were made to determine the heating effectin living tissue of laser light having a wavelength of approximately 808nanometers. A GaAlAs laser source of 808-nanometer light was placed indirect contact with the skin of the heads of live rabbits and rats. Thelaser source had an approximately Gaussian beam profile with a beamdiameter of 2.5-4.0 millimeters (1/e²). Thermocouple probes (ModelBat-12 from Physitemp Instruments Inc. of Clifton, N.J.) were placed inthe subcutaneous tissue and below the dura and measurements wererecorded at various power densities. The results of these measurementsare shown in Table 3:

TABLE 3 Exposure Temperature Animal Probe location Dose time increaseRat Subcutaneous 15 mW/cm² 4 minutes approximately 3° C. Rat Subdural 15mW/cm² 4 minutes approximately 1° C. Rat Subcutaneous 75 mW/cm² 4minutes approximately 7° C. Rat Subdural 75 mW/cm² 4 minutesapproximately 7° C. Rabbit Subcutaneous 7.5 mW/cm²  5 minutes less than0.5° C. Rabbit Subdural 7.5 mW/cm²  5 minutes less than 0.5° C. RabbitSubcutaneous 37.5 mW/cm²   5 minutes approximately 5.5° C. RabbitSubdural 37.5 mW/cm²   5 minutes less than 0.5° C.

There is minimal heating (e.g., less than 0.5° C.) in the subduralregion at four times the therapeutic energy density. The “heat sink”effect of living tissue that minimizes possible heating in the cortex issignificantly larger in humans than in rats or rabbits, due to thelarger heat sink and blood flow volume, which further limits theundesirable effects of heating in the treated region of the brain.Therefore, in certain embodiments described herein, a therapeutic dosageof energy is delivered to the target area of the brain withoutundesirable heating of the dura.

Implantation of In Vitro Irradiated Cells

In certain embodiments, a method is provided for treating damage orillness in the central nervous system in a mammal or human, comprisingdelivering an effective amount of light energy to an in vitro culturecomprising progenitor cells, and implanting the cells into the centralnervous system of a mammal or human, wherein delivering an effectiveamount of light energy includes delivering light having a wavelength inthe visible to near-infrared wavelength range and a power density of atleast about 0.01 mW/cm² to the cells in culture.

In certain embodiments, treatment of a patient includes implantation ofprogenitor cells into the central nervous system (“CNS”) of the patient.Following implantation, the progenitor cells differentiate to form oneor more cell types of the central nervous system. The implanted cellsmay serve any of a variety of purposes, including replacement of cellsor tissues that have been irreparably damaged, repair of a portion ofthe CNS, enhance the production of important CNS neurochemicals such asdopamine, seratonin, endogenous opioid peptides, and the like.Implantation of progenitor cells may be performed alone, or it may bedone in combination with the methods of enhancing neurologicfunctioning, as described herein.

The term “progenitor cell” as used herein has its broadest reasonablemeaning, including but not limited to (1) a pluripotent, orlineage-uncommitted, progenitor cell, a “stem cell” or “mesenchymal stemcell”, that is potentially capable of an unlimited number of mitoticdivisions to either renew its line or to produce progeny cells that willdifferentiate into any of a variety of cells, including cells of thecentral nervous system including neural cells such as astrocytes,oligodendrocytes, and neurons; or (2) a lineage-committed progenitorcell produced from the mitotic division of a stem cell which willeventually differentiate into a neural cell. Unlike the stem cell fromwhich it is derived, the lineage-committed progenitor is generallyconsidered to be incapable of an unlimited number of mitotic divisionsand will eventually differentiate into a neural cell or other CNS cell.

The term “differentiation” as used herein has its broadest reasonablemeaning, including but not limited to the process whereby anunspecialized, pluripotent stem cell proceeds through one or moreintermediate stage cellular divisions, ultimately producing one or morespecialized cell types. Differentiation thus includes the processwhereby precursor cells, e.g., uncommitted cell types that precede thefully differentiated forms but may or may not be true stem cells,proceed through intermediate stage cell divisions to ultimately producespecialized cell types. Differentiation encompasses the process wherebymesenchymal stem cells (MSC) are induced to differentiate into one ormore of the committed cell types comprising the central nervous system,in vivo or in vitro.

The terms “growth chamber” and “cell culture chamber” as used herein areused interchangeably and are to be interpreted very broadly to refer toany container or vessel suitable for culturing cells, including, but notlimited to, dishes, culture plates (single or multiple well),bioreactors, incubators, and the like. Certain embodiments describedherein utilize a cell culture apparatus such as is described in U.S.patent application Ser. No. 10/700,355, filed Nov. 3, 2003 andincorporated by reference herein in its entirety.

In certain embodiments, progenitor cells are inoculated and grown in acell culture in vitro, using parameters including power density asdiscussed above. Because the light energy is applied directly to thecell culture in vitro and does not travel through intervening bodytissue, the power density selected to be delivered to the cell isgenerally equal to the power density of the light energy as it isemitted from the light apparatus. If lenses, filters, dispersiongratings, or any other material lies between the light source and thecells, any absorption or dispersion of the light energy by such materialshould be taken into account and the applied light energy adjusted, ifneeded, to account for the material. In certain embodiments, the treatedcells are implanted following treatment. In certain other embodiments,at least some treated cells remain in culture to maintain the cell linefor later use.

After in vitro treatment of cells using electromagnetic energy, thecells are transplanted or implanted to a recipient site in a patient. Incertain embodiments, the treatment prior to transplantation orimplantation includes culturing cells sufficient for implantation. Therecipient site may be a site of injury, illness, or defect, or it may bea region of relatively healthy tissue. In certain embodiments, therecipient site and/or the region surrounding such site is treated withlight energy according to the methods described supra, before and/orafter implantation to enhance the rate at which the implanted cells areintegrated with surrounding tissue at the recipient site.

In certain embodiments, progenitor cells such as stem cells are treatedwith electromagnetic energy as noted above and then implanted into thebrain of a patient, such a patient who is at risk for Parkinson'sdisease, exhibits symptoms of Parkinson's disease, and/or has beendiagnosed with Parkinson's disease. Following implantation, therecipient site is optionally treated with electromagnetic energy,including directly at the recipient site or through the skull at therecipient site, or some other portion of the brain, such as the cortex.The transplanted cells produce dopamine to treat, or lessen the symptomsand/or delay onset of Parkinson's disease in the patient.

In certain embodiments, progenitor cells are treated withelectromagnetic energy and implanted or transplanted at a site ofphysical trauma to the spinal cord or one or more nerves of a patient.Following implantation, the recipient site is optionally treated withelectromagnetic energy. Such optional treatment may include treatmentimmediately following implantation and/or one or more treatment periodsfollowing implantation. The transplanted cells help repair damage to thespinal cord or nerve(s) such that the recovery or prognosis is enhancedin patients having implanted progenitor cells as compared with those whodo not receive such implants.

Treatment of Heat Stroke

In certain embodiments, a method prevents heat stroke in a subject. Theterm “preventing” in this context includes reducing the severity of alater heat stroke in a subject that has undergone treatment, reducingthe incidence of heat stroke in individuals who have undergonetreatment, as well as reducing the likelihood of onset heat stroke in asubject that has undergone treatment. The method includes deliveringlight energy having a wavelength in the visible to near-infraredwavelength range through the skull to at least one area of the brain ofa subject, wherein the wavelength, power density and amount of the lightenergy delivered are sufficient to prevent, reduce the severity, orreduce the incidence of heat stroke in the subject.

While certain embodiments of phototherapy are described herein inconjunction with various theories and potential action mechanisms, asthey presently appear to the inventors, the scope of the claims of thepresent application is not to be construed to depend on the accuracy,relevance, or specifics of any of these theories or potential actionmechanisms. Thus the claims of the present application are to beconstrued without being bound by theory or by a specific mechanism.

Various embodiments of the present invention have been described above.Although this invention has been described with reference to thesespecific embodiments, the descriptions are intended to be illustrativeof the invention and are not intended to be limiting. Variousmodifications and applications may occur to those skilled in the artwithout departing from the true spirit and scope of the invention asdefined in the appended claims.

1. A method of treating a patient having neurologic function affected by Parkinson's disease, the method comprising: providing a patient having neurologic function affected by Parkinson's disease; and delivering electromagnetic radiation noninvasively through the scalp and the skull of the patient to at least one portion of the brain of the patient, the light energy having a wavelength in the visible to near-infrared wavelength range, wherein the wavelength, power density, and amount of the light energy delivered to the at least one portion of the brain are sufficient to reduce the severity of symptoms of Parkinson's disease in the patient.
 2. The method of claim 1, wherein delivering the electromagnetic radiation comprises: identifying at least about 10 treatment sites on the patient's scalp; directing an electromagnetic radiation source to each of the treatment sites; and propagating electromagnetic radiation from the source to each treatment site, the electromagnetic radiation having a wavelength within a range between about 800 nanometers and about 830 nanometers.
 3. The method of claim 2, wherein identifying at least about 10 treatment sites comprises placing a support on the patient's head, the support comprising indicia of locations of the treatment sites.
 4. The method of claim 3, wherein the indicia comprise openings in the support.
 5. The method of claim 2, wherein propagating electromagnetic radiation comprises sequentially propagating electromagnetic radiation at each treatment site one at a time.
 6. The method of claim 2, wherein the at least one portion of the brain comprises an area exhibiting neurodegeneration.
 7. The method of claim 2, wherein the at least one portion of the brain comprises an area associated with a particular cognitive or motor function.
 8. The method of claim 2, wherein the at least one portion of the brain comprises substantially the entire brain.
 9. The method of claim 1, wherein the power density is between 0.01 mW/cm² and 100 mW/cm² at a depth of approximately 2 centimeters below the dura.
 10. The method of claim 1, wherein the power density is at least 0.1 mW/cm² at a depth of approximately 2 centimeters below the dura.
 11. The method of claim 1, wherein the wavelength is between about 630 nanometers and about 1064 nanometers.
 12. The method of claim 1, wherein delivering the electromagnetic radiation, when applied to members of an irradiated group of patients, produces at least a 2% average difference in a neurologic function scale between the irradiated group of patients and a group of patients having Parkinson's disease and receiving a placebo.
 13. The method of claim 12, wherein the neurologic function scale is the Unified Parkinson's Disease Rating Scale (UPDRS).
 14. The method of claim 1, wherein delivering the electromagnetic radiation causes an improvement of mitochondrial function in irradiated neurons.
 15. The method of claim 1, wherein delivering the electromagnetic radiation increases ATP production by irradiated neurons.
 16. A method of treating or preventing Parkinson's disease, the method comprising: noninvasively irradiating at least a portion of a patient's brain with electromagnetic radiation transmitted through the scalp, the electromagnetic radiation having a power density between 0.01 mW/cm² and 100 mW/cm² at a depth of approximately 2 centimeters below the dura.
 17. A method of treating a patient, the method comprising delivering electromagnetic radiation noninvasively through the scalp and the skull to at least one portion of the brain of the patient, the light energy having a wavelength in the visible to near-infrared wavelength range, wherein the wavelength, power density, and amount of the light energy delivered to the at least one portion of the brain are sufficient to prevent, reduce the severity, or reduce the incidence of Parkinson's disease in the patient.
 18. A method of preventing Parkinson's disease in a patient, the method comprising: providing a patient having a predisposition towards contracting Parkinson's disease; and delivering electromagnetic radiation noninvasively through the scalp and the skull of the patient to at least one portion of the brain of the patient, the light energy having a wavelength in the visible to near-infrared wavelength range, wherein the wavelength, power density, and amount of the light energy delivered to the at least one portion of the brain are sufficient to reduce a probability of the patient contracting Parkinson's disease.
 19. A method of treating the central nervous system of a patient, the method comprising: identifying a patient exhibiting symptoms of damage to the central nervous system due to Parkinson's disease; irradiating an in vitro culture comprising progenitor cells with electromagnetic radiation having a wavelength in the visible to near-infrared wavelength range and a power density of at least about 0.01 mW/cm²; and implanting the irradiated cells into the central nervous system of the patient. 